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CDRH's 510k Working Group Preliminary Report: Finding 5

A GLIMPSE AT THE FUTURE?
A Cycle of 510(k) Whitepapers by Nancy J Stark and Kathleen Johnson

In August 2010, CDRH's 510(k) Working Group published a preliminary report consisting of more than 60 recommendations grouped under seven findings aimed at improving the Center's effectiveness in implementing its missions. Will the recommendations work? Do they comprise a forward-thinking strategic plan for the device industry? Herein you'll find CDG's summation of Finding 3 and part of Finding 4, along with our opinions of their worth.

Finding 5: CDRH's knowledge management infrastructure is limited

Neither Center staff nor 510(k) submitters have access to meaningful information
The only comprehensive electronic source of non-public information on prior 510(k) reviews available to Center staff is a database of archived image files. The database is searchable only by 510(k) number. To find information within each file, staff must conduct a labor-intensive, file-by-file text search. Without looking through each file individually, it is impossible to determine what predicate(s) the reviewer used as the basis for a substantial equivalence determination, and what the rationale for the decision was. Moreover, archived files contain varied levels of detail. Older 510(k) submissions and review memoranda are inconsistent in format and content, and many of them are handwritten.

[1] Enhanced 510k database needed
The Working Group recommends that both internal and public information systems be enhanced.

CDG agrees and further suggests the databases be made available through PubMed, Embase, or even Google where the ability to limit date ranges, use 'not' operators, turn on keyword explosion, use fuzzy logic, and use sophisticated text-search tools are available. Furthermore, the database in its entirety should be downloadable to Excel. The Summaries of Safety and Effectiveness or 510(k)s themselves should be keyworded by K number, product code, predicates, generic and brand names to allow for 'family trees' or 510k pedigrees to be constructed. The information should be available all the way back to 1976, and not stop at 2002.

CDG can write your 510(k)
CDG's extensive Network Staff has expertise in writing 510(k)s in a wide variety of therapeutic, management, or diagnostic areas. My co-author, Kathleen Johnson is a regulatory consultant with more than 10 years experience in medical devices. CDG has capabilities in regulatory submissions, clinical research, toxicology, biostatistics, information research, medical writing, design control—we focus exclusively on medical device pre-approval issues.

Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or [email protected].

[2] Product Codes, also known as classification numbers
Product codes are the underpinning for CDRH’s information management systems. They are the primary tool for organizing medical device information in CDRH’s databases, and staff across the Center rely on product codes in their day-to-day work. Product codes are used for tracking and analysis of medical device data across a device’s total product life cycle, including information from premarket submissions, adverse event reports, device recalls, inspections, and compliance actions. Review staff and 510(k) submitters use product code searches to identify and obtain information about potential predicate devices. Product codes were intended to provide more granular distinctions than the general descriptive language provided in the classification regulations. However, inconsistencies in the way product codes are assigned make it difficult to access meaningful device information.

The origin of "product codes" is so old even the Working Group could not give it an accurate reference; a day of research revealed the term "classification number" on FDA Form 2892, which was introduced in 1977 in 21 CFR 807.26, somehow transformed itself into the term "product code" (for a three letter, non-numeric code) at some point in time.

Working Group Recommendations
The Working Group recommends that the agency develop procedures for assigning product codes consistently and that special attention be given to IVD multiplex devices.

CDG agrees and suggests the search engine for product codes be improved. At this time, in order to find a predicate device you can: 1) search keywords in the classification database (simple search) to get a list of product codes and regulation numbers that match your keywords, 2) then search on the product code in the 510(k) database to find possible predicates for your new device. But this method is laborious, time-consuming, and the list that results may not contain good matches for your device. Furthermore, if your device is made of multiple components you will have to do a separate search for each component. And the list does not go back to 1976, so a comprehensive search is not possible. We also suggest that the device listing Form FDA 2892 ask for a product code rather than a classification number to dispel confusion, and that a history of the relationship between the two terms be clarified.

[3] 510(k) Databases
The 510(k) database is not easily searchable for either reviewers or submitters. Lacking a reliable source of accurate information, 510(k) submitters may be forced to look at how the predicate is advertised, which does not necessarily reflect the intended use for which it was cleared. Once cleared, device 510(k) are not accompanied by a revewer-prepared Decision Summary or a reviewer-prepared Summary Basis of Approval, as are IVD 510(k)s or pharmaceuticals. These Summaries are written by the FDA reviewer and capture the thought process and rationale for clearance.

 The data are from page 39 of the Working Group Preliminary Report

 
Working Group Recommendations
The Working Group recommends that CDRH develop a publicly available, easily searchable database that includes, for each cleared device, a verified 510(k) summary, photographs and schematics of the device (to the extent that they do not contain proprietary information), and information showing how cleared 510(k)s relate to each other and identifying the premarket submission that provided the original data or validation for a particular product type.

CDG believes that if a decently searchable 510(k) database were made available to submitters, the quality of submissions and appropriateness of predicates would improve automatically and the time to clearance would decrease. The database should go as far back as 1976 to facilate comprehensive searches. No further changes or requirements should be made until a functional seach engine is developed.

CDG further recommends that a reviewer-prepared Decision Summary be prepared for every cleared 510(k) as an enhancement to the 510(k) Quality Review Program (I96-1). It should be made available to the public, along with the company-prepared 510(k) Statement or Summary. This would enhance quality in 510(k) submissions and consistency in 510(k) clearances.

[4] Final Device Labeling
One frustration for FDA is that final device labeling and updates to labeling are not routinely reviewed; hence labeling may be inconsistent with, or over-interpret, cleared indications.

Working Group Recommendatons
The Working Group recommended the agency explore the requiring manufacturers to submit final device labeling to FDA by the time of clearance or within a reasonable period of time after clearance, and also to provide regular, periodic updates to device labeling.

CDG's concern is that requiring final labeling before a 510(k) is cleared would merely add to the timeframe for clearance. Annually updating device labeling—when taken together with the previous recommendations for annual updates for device modifications and the recommendation that all scientific information be included in the original submission, regardless of whether or not it supports an argument of substantial equivalence—is tantamount to requiring an annual 510(k) supplement similar to that required for PMAs. It is unduly burdensome for manufacturers of 510(k) devices and an already overburdened FDA staff could not handle the additional data.

We suggest that FDA update the 1997 guidance document "Deciding When to Submit a 510(k) for a Change to an Existing Device" and make available an online webcast to educate manufacturers about its contents.

[5] 510(k) Ownership
CDRH’s databases rarely reflect changes in 510(k) ownership that occur after clearance, largely because the Center is not typically notified of transfers of ownership.

Working Group Recommendations
The Working Group recommends the agency develop guidance and regulations regarding appropriate documentation of transfers of 510(k) ownership. The Center should update its 510(k) database in a timely manner when a transfer of ownership occurs. CDG, as well as a majority of public comments, support the recommendation.

CDRH Missions
The Center for Devices and Regulatory Health has two important missions: 1) to protect the public health, and 2) to foster medical device innovation. Their difficult job is to keep these missions in balance, never compromising one in favor of the other. Do you have the original citation for fostering medical innovation?

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

CDRH's 510(k) Working Group—Finding 4

A GLIMPSE OF THE FUTURE?
A Cycle of 510(k) Whitepapers by Nancy J Stark and Kathleen Johnson

The Center for Devices and Regulatory Health has two important missions: 1) to protect the public health, and 2) to foster medical device innovation. Their difficult job is to keep these missions in balance, never compromising one in favor of the other.

In August 2010, CDRH's 510(k) Working Group published a preliminary report consisting of more than 60 recommendations grouped under seven findings aimed at improving the Center's effectiveness in implementing its missions. Will the recommendations work? Do they comprise a forward-thinking strategic plan for the device industry? Herein you'll find CDG's summation of Finding 3 and part of Finding 4, along with our opinions of their worth. If you wish to comment, please do so below.

Finding 4: It is challenging for reviewers to obtain the information it needs to make well-supported clearance decisions

[5] Improper use of recognized standards—require a summary of testing
Section 514(c)(1) of the Act describes the possibility of using, as part of a 510(k) submission, consensus standards that have been entirely or partially recognized by FDA. This section states, “[FDA] shall, by publication in the Federal Register, recognize all or part of an appropriate standard established by a nationally or internationally recognized standard development organization for which a person may submit a declaration of conformity in order to meet a premarket submission requirement or other requirement under this Act to which such standard is applicable.”

Working Group Issues
The problems are that: 1) a device may raise questions of safety and performance not addressed by the consensus standard; the standard provides only partial evidence of substantial equivalence, 2) submitters may not use the most current version of a standard, they may not be able to determine which sections of the standards are recognized and which are not (you must turn to the supplemental information sheets), and 3) submitters do not always indicate how they have used the standard or deviated from the standard.

CDG Comments: The recognized version of a standard, not the current version, should be used. The 510(k) Manual should be updated to discuss the proper use of consensus standards and the "Standards Data Report Form for 510(k)s" should be modified to provide a place for summary information and all other relevant information FDA requires.

CDG can write your 510(k)

CDG's extensive Network Staff has expertise in writing 510(k)s in a wide variety of therapeutic, management, or diagnostic areas. My co-author, Kathleen Johnson is a regulatory consultant with more than 10 years experience in medical devices. CDG has capabilities in regulatory submissions, clinical research, toxicology, biostatistics, information research, medical writing, design control—we focus exclusively on medical device pre-approval issues.

Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or [email protected].

[6] Incomplete information—how much is enough?
Current regulations require 510(k) submissions to provide "data to support the statement" regarding substantial equivalence to a predicate device. Under PMA regulations, PMA applications are explicitly required to contain a summary of all information known concerning the safety and/or effectivenes of the device under review. FDA's concern is that submissions may contain biased information, including only clinical or scientific information that supports device equivalency.

Working Group recommendations
The Working Group recommends that 21 CFR 807.87 be revised to explicitly require 510(k) submitters to provide a list and brief description of all scientific information regarding the safety and/or effectiveness of a new device known to or that should be reasonably known to the submitter.

CDG comments: The recommendation to review all available literature is not in keeping with the original intention of the Act, which was to demonstrate substantial equivalence to a predicate. It sounds like a Clinical Evaluation Report for every medical device in Europe. The result could inundate FDA with so much information that an already stressed Agency would increase its review times rather than become more efficient.

Summarizing data generated by other parties on similar, but not equivalent devices, is not helpful; summarizing data generated by other parties on equivalent devices but dissimilar test methods is not helpful. Much information is developed using early design or prototype devices. Would the recommendation require a review of every document in the design history file and before? It has the feel of a PMA, where safety and performance are established de novo.

Listen to Experts Janice Hogan and Yarmela Pavlovic
Discuss "The Successful 510(k)"

Listen to experts Janice Hogan, Esq and Yarmela Pavlovic, Esq. present the whys and hows of crafting a successful 510(k) on CD or OnDemand and take advantage of their vast experience. Their detailed and thorough presentation covers: 1) the legal framework, 2) finding predicates, 3) chosing the right claim, introducing new features, 4) assessing data requirements, 5) software and combination products, 6) dealing with a not-substantially equivalent (NSE) determination, 7) handling device modifications, and 8) seeing the 510(k) from the reviewers perspective. You'll receive the slide deck, video/audio recording, and links to important guidances. Order here.

[7] Type and level of evidence needed
The reviewer's first step is to determine if the device and predicate have the same intended use. However, once this is done, most devices have either different indications for use and/or different technological characteristics than the predicate, and FDA may want data to show that any differences have not altered the intended use or significantly affected the safety and/or effectiveness of the device. In most cases data from bench and/or animal testing is sufficient to complete the argument of safety and effectiveness, but in some cases the Agency wants additional data.

Working Group recommendations
The Working Group recommends the agency develop guidance defining a subset of devices, i.e. Class IIb devices, for which clinical information, manufacturing information, or post-marketing information would be typically necessary.

CDG has already stated that it disagrees with defining Class IIa and Class IIb devices because it will lead to confusion with European Class IIa and IIb device classification schemes. If clinical, manufacturing, or post-market information is necessary to successfully argue safety and effectiveness, the agency can address this via a "Super" 510(k). As prevsiouly stated, the regulation numbers of devices and the required information for Super 510(k)s should clearly defined; the information requirements cannot change with each submission.

[8] Clinical information
The Working Group acknowledges there is common misunderstanding as to what constitutes clinical data. Yet within the space of four paragraphs on pages 76-77 of the report the Working group refers to "clinical information", "clinical data", "clinical evidence", "clinical investigation", and "clinical study". According to CDRH staff, submitters sometimes cite the definition of “valid scientific evidence” together with the “least burdensome” provisions of the Act, claiming that it is sufficient for them to provide any type or level of evidence that meets the definition of “valid scientific evidence” with the lowest possible level of burden, even if such evidence fails to provide "reasonable assurance" of safety and effectiveness.

 

 
Working Group recommendations
The Working Group recommends a “Class IIb” guidance provide greater clarity regarding the circumstances in which the agency will request clinical data in support of a 510(k), what type and level of clinical data are adequate to support clearance, and to define clinical data. Would this mean that all IVD 510(k)s are Class IIb?

CDG recognizes there are situations in which new clinical data may be necessary to establish substantial equivalence and demonstrate safety and effectiveness.

For the most part, however, substantial equivalence, safety, and performance can be clearly established with valid scientific evidence obtained from bench and animal data. Needlessly requesting new human clinical data is unethical. All clinical trials expose human subjects to risk by their very definition. It is not that not conducting a clinical trial should be justified, but that the very act of conducting a clinical trial should be justified.

By needlessly raising the bar to 510(k) clearance, FDA neglects is obligation to foster medical device innovation.

With regard to clinical information, FDA should harmonize its definitions of clinical information with Europe and GHTF so that communication between submitters and reviewers can be clear. In the Europe and GHTF world clinical information is data from the literature, research in humans is a clinical investigation (study or trial may be used colloquially), clinical evaluations are reviews of clinical information and clinical investigations and the risk management system altogether.

[9] Postmarket information
CDRH feels that for certain devices, including novel or particularly complex technologies, it is not feasible to conduct a large-scale clinical trial prior to clearance [does this mean such devices are now cleared without adequate clinical data?] They feel it is necessary to collect additional data after clearance in order to better evaluate the safety and effectiveness of a device over a longer time period, or in a wider patient population.

CDRH has the authority to require postmarket surveillance studies (also called Section 522 studies) as a condition of 510(k) clearance for devices that are expected to have significant use in pediatric populations, but there is no explicit authority for CDRH to order Section 522 studies as a condition of premarket clearance in other situations.

Working Group recommendations
The Working Group recommends the Agency seek greater authority to require postmarket surveillance studies as a condition of clearance for certain devices.

CDG comments: The public health may benefit from postmarket registry studies for certain long-term use devices or devices with very long-lasting effects, however the decision to conduct such studies should be that of the manufacturer and not a condition for clearance.

The agency should continue to develop a unique device identification (UDI) system. There is a vast store of information collected everyday from Medicare billing records, Medicaid billing records, the Health Care Utilization Program (HCUP), and other public information sources, which will allow "real-world" anonymized data on device use and outcomes to be searched, sorted, and correlated.

[10] Manufacturing process information
Working Group recommendations
Because 37% of device recalls are associated with manufacturing problems, the Working Group recommends CDRH develop guidance to provide greater clarity regarding what situations may warrant the submission of manufacturing process information as part of a 510(k), and include a discussion of such information as part of its “class IIb” guidance. The Working Group further recommends the agency seek authority to withhold clearance on the basis of a failure to comply with good manufacturing practice requirements in certain situations.

CDG comments: There are situations, as with novel materials, when manufacturing process and design control information should be part of the 510(k) and that such situations should be addressed in a guidance.

A requirement to have evidence of a good manufacturing practice system in place prior to clearance moves the 510(k) process into the arena of a PMA. Many of the proposals by the Working Group blur the line between the 510(k) and PMA processes. The distinction is clear in the Act and should be honored by the Agency.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

 

CDRH's 510(k) Working Group—Findings 3 & 4a

A GLIMPSE OF THE FUTURE?
A Cycle of 510(k) Whitepapers by Nancy J Stark and
Kathleen Johnson

The Center for Devices and Regulatory Health has two important missions: 1) to protect the public health and 2) to foster medical device innovation. Their difficult job is to keep these missions in balance, never compromising one in favor of the other.

In August 2010, CDRH's 510(k) Working Group published a preliminary report consisting of more than 60 recommendations grouped under seven findings aimed at improving the Center's effectiveness in implementing its missions. Will the recommendations work? Do they comprise a forward-thinking strategic plan for the device industry? Herein you'll find CDG's summation of Finding 3 and part of Finding 4, along with our opinions of their worth. If you wish to comment, please do so at our blog.

 
Finding 3: the de novo pathtway is important and has not been optimally used across the Center.

The de novo process is an essential tool but difficult-to-use tool
The de novo classification process was established under FDAMA to allow for the 510(k) clearance of devices for which there is no predicate but whose risks do not warrant a PMA approach. The problem with the current system is that a device must first be classified as a Class III through a formal process. The issue is how to expedite classification.

The Working Group recommendation
CDRH reform its implementation of the de novo classification process to provide a practical, risk-based option that affords an appropriate level of review and regulatory control. While the number of de novo requests increases every year (there were 15 in 2009) the review process has become an incredible 2-3 years!

CDG Comments: We agree with the Working Group recommendation and further recommend that the Agency develop a separate de novo application which would include: 1) evidence of no predicate for the intended use and/or technology, 2) demonstration of low risk through design control and biological safety information, and 3) a mechanism for de novo meetings with the Agency. The application should be reviewed within 60 days of submission.

Typically CDRH develops device-specific guidance documents as special controls for de novo devices. CDRH should develop a single generic set of controls that could serve as the baseline. Device-specific guidelines can be added later, as needed.

This would give the Agency an avenue to either quickly classify a device as Class I or II via the de novo process or determine that the device is actually a Class III device.

 

Finding 4: It is challenging for reviewers to obtain the information it needs to make well-supported clearance decisions.

Class IIb Devices versus a "Big Mac" 510(k)
Working Group recommendations
The Working Group recommends creation of a new "class IIb" device classification.

CDG is baffled that the Working Group thinks a new "class IIb" classification is necessary or would even helpful to their obtaining sufficient levels of information about a device to make fully informed decisions.

First, it would add to global confusion. The European Union has a Class IIa and Class IIb device classification system and the EU Class IIb and US Class IIb are unnlikely to be the same. Because most companies do business globally, we should at least be creative enough to think of a new phrase.

And why not build on what we already have: a Special 510(k), Abbreviated 510(k), and Traditional 510(k). If we follow our existing pattern and instead create a new type of 510(k) called a "Super 510(k)" or "510(k) Plus." The Super 510(k) would describe additional information, over and above a traditional 510(k), that would be required for certain, significant-risk Class II devices. A new category of 510(k) can be structured to meet FDA needs, provide more options for the manufacturer, and avoid confusion with the world's second largest device market. We would like to see clear identification of the devices that require clearance under the "Super 510(k)" and defined requirements for data.

Device modifications: to report or not report?
Under current regulations, manufacturers are only required to submit new 510(k)s for device modifications when the modification "could significantly affect the safety or effectiveness of the device" or there has been a "major change or modification to the intended use of the device." The Agency has observed that minor, incremental modifications sometimes accrue to the point that safety, effectiveness, or intended use are affected. Also, there is concern that manufacturers misinterpret the regulation to mean that a new 510(k) is only necessary if a modification definitely does affect safety and/or effectiveness. There is also concern that manufacturers misinterpret the regulation to mean that a new 510(k) is only necessary if a modification could negatively affect safety and/or effectiveness.

When a 510(k) is submitted for a particular modification, CDRH must evaluate not only the effect of that modification itself on the device’s safety and effectiveness, but also the cumulative effect of any unreported modifications that preceded it. There is no explicit requirement for submitters to list the modifications that have been made since the last clearance. This can create challenges for review staff and may result in requests for additional information in the midst of a review.

Working Group recommendations
The Working Group recommends CDRH revise existing guidance to clarify what types of modifications do or do not warrant submission of a new 510(k), and, for those modifications that do warrant a new 510(k), what modifications are eligible for a Special 510(k) (i.e. declaration of conformity to design controls in lieu of providing detailed performance data to FDA as part of a 510(k).) The guidance should clarify that a new 510(k) is also required for changes that potentially could have a positive effect, because what was expected to have a positive impact may in fact create new risks that would not be detected without an adequate assessment.

Finally, the Working Group recommends that CDRH require each manufacturer to provide regular, periodic updates to the Center listing modifications made without 510(k) submission.

CDG comments: Modernizing guidances as to what type of modification requires a new 510(k) submission would be useful. When a 510(k) is submitted, it is reasonable to expect the submitter to identify all interim modifications in both design and/or labeling made since the previous submission.

Periodic modification reporting would result in a huge work overload for both manufacturers and reviewers. Neither party has the human or financial resources to manage regular reporting.

CDG can write your 510(k)

CDG's extensive Network Staff has expertise in writing 510(k)s in a wide variety of therapeutic, management, or diagnostic medical device areas. My co-author, Kathleen Johnson has more than 12 years experience in medical device regulatory affairs. CDG has capabilities in regulatory submissions, clinical research, toxicology, biostatistics, information research, medical writing, design control—we focus exclusively on medical device pre-approval issues.

Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or [email protected].

Quality of submissions—crafting an argument
In this section the Working Group takes great pains to avoid stating outright that some submitters can't write: we do not make logical and scientifically developed arguments for safety and effectiveness (i.e. we don't apply the scientific method when structuring our arguments), we are disorganized, and we omit information that is clearly required.

CDRH reviewers state: "...information contained in the “Device Description” section of a 510(k) is often a general summary, and it frequently does not provide an adequate level of detail about the new device...." and "...or many 510(k)s, information provided in one section is inconsistent with information provided in another."

Working Group recommendations
The Working Group recommends the agency adopt the use of an "assurance case" framework for 510(k) submissions. An assurance case is defined as a documented body of evidence that provides a convincing and valid argument that a specified set of critical claims regarding a device's safety and performance are adequately justified. The definition parallels three steps of the scientific method.

 
Further, the Working Group recommends that both photographs and schematics be included with a submission, and that manufacturers retain at least one unit of a device and make it available to the agency for current or future reviews (e.g. when the device is cited as a predicate.)

CDG comments: FDA should update the 510(k) Manual (FDA publication 95-4158) and make it available under "guidances" in Device Advice. This document provides detailed guidance of what each section of a 510(k) should include. There is no need to develop yet another model, when a sufficient and familiar model already exists. Kathleen has used this manual as her guide in developing numerous, successfully cleared 510(k)s.

 
We searched for "510(k) Manual" in Device Advice and it isn't there. We searched for "510(k) Manual" in Google and it isn't there. Kathleen had a copy in her library so we could find the FDA publication number. When we searched for "FDA publication 95-4158" in Google we found a copy under FDA dockets. We were amazed that the 510(k) Manual was so difficult to find and not available at all under Device Advice.

FDA has a website for most of its databases, but the database for guidance documents—surely a key database for good 510(k) submissions—is not there. The website is called FDA Databases and you can see from the image above that there is no tab for guidances!

Part of the problem is that new companies can't find the information they need to tell them how to prepare a 510(k). Maybe FDA should sponsor a public workshop, live or available free as webcasts, to educate new submitters about requirements and expectations for 510(k) submissions.

Listen to Experts Janice Hogan and Yarmela Pavlovic
Discuss "The Successful 510(k)"

As useful as when it was first recorded, Janice Hogan and Yarmela Pavlovic present the whys and hows of crafting a successful 510(k). Listen on CD or OnDemand and take advantage of their vast experience. Their detailed and thorough presentation covers: 1) the legal framework, 2) finding predicates, 3) choosing the right claim, introducing new features, 4) assessing data requirements, 5) software and combination products, 6) dealing with a not-substantially equivalent (NSE) determination, 7) handling device modifications, and 8) seeing the 510(k) from the reviewers perspective. You'll receive the slide deck, video/audio recording, and links to important guidances. Order here.

CDG disagrees that exemplar devices be retained for current or future reviews. Some devices cost many thousands of dollars, some fill an entire room, and some are not stable. Retaining examples would be unduly burdensome and in some cases an impossibility. Furthermore, one manufacturer should not be compelled to make an example device available to FDA so that FDA can have it available for reviewing a submission from another manufacturer.

Improper use of recognized standards—require a summary of testing
Section 514(c)(1) of the Act describes the possibility of using, as part of a 510(k) submission, consensus standards that have been entirely or partially recognized by FDA. This section states, “[FDA] shall, by publication in the Federal Register, recognize all or part of an appropriate standard established by a nationally or internationally recognized standard development organization for which a person may submit a declaration of conformity in order to meet a premarket submission requirement or other requirement under this Act to which such standard is applicable.”

Working Group Issues
The problems are that: 1) a device may raise questions of safety and performance not addressed by the consensus standard; the standard provides only partial evidence of substantial equivalence, 2) submitters may not use the most current version of a standard, they may not be able to determine which sections of the standards are recognized and which are not (you must turn to the supplemental information sheets), and 3) submitters do not always indicate how they have used the standard or deviated from the standard.

CDG Comments: The recognized version of a standard, not the current version, should be used. The 510(k) Manual should be updated to discuss the proper use of consensus standards and the "Standards Data Report Form for 510(k)s" should be modified to provide a place for summary information and all other relevant information FDA requires.

Where's the rest? The last five recommendations under Finding 4 will come out next week. Got something to add? Please comment below.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc 

 

CDRH's 510(k) Working Group—Findings 1 & 2



A GLIMPSE OF THE FUTURE?
A Cycle of 510(k) Whitepapers by Nancy J Stark and Kathleen Johnson with
IVD input from Gail Radcliffe

I have to see something visually to really grasp it. It took me nearly a day to reconstruct the timeline presented here and I doubt that it is comprehensive. It's value, I think, is that it emphasizes how events have been happening at CDRH in rapid succession and that respected public groups, such as Consumer's Union, have been complaining for a long time.

In February 2010, CDRH held a two-day "town hall" meeting called Strengthening the Center in which they presented several of their concerns and invited selected industry and user representatives to present theirs. This was followed by two internal surveys—one from the 510(k) Working Group and the second from the Task Force on Utilization of Science in Regulatory Decision Making—published in August 2010.

The 510(k) Working Group's Preliminary Report—What's it to me?
The 510(k) Working Group preliminary report is 120 pages in length. It took me a good four days to make my way through it in detail. My goal in this first cycle of whitepapers is to reduce the report to a manageable chunk of reading, yet to give you a good sense of FDA's probable direction. And, because you are mostly device clinical and regulatory professionals, I intend to speculate on what it may mean in your daily work-life. I've invited my regulatory colleagues, Kathleen Johnson (medical devices) and Gail Radcliffe (in-vitro diagnostics—IVDs), to keep me out of trouble.

The Working Group had seven findings and made a number of recommendations for improvement within those findings, many of them will make our lives easier. But for some firms there will need to be a re-thinking of regulatory procedures if the recommendations are implemented.

Finding 1: There is insufficient clarity with respect to the definition of “substantial equivalence”

The terms "intended use" and "indications for use" are poorly defined
Substantial equivalence begins with determining that a device and its predicate have the same intended use. For IVDs Gail tells me a statement of intended use is required in the electronic submission and is then incoporated into the IVD Decision Summary. It is defined as a description of what the manufacturer intended to measure with a certain test, and typically consists of the following elements: 1) mechanism of assay, 2) what is being assayed, 3) the population being assayed, 4) whether the assay is quantitative or qualitative, 5) whether the assay is an adjunct or a replacement for the gold standard, and 6) what is the next step (surgery, further diagnosis, and the like.)

For non-IVDs, 21 CFR 801.4 defines intended use as the "objective intent of the persons legally responsible for the labeling of the device" and 21 CFR 814.20(b)(3)(i)] defines indications for use as "a general description of the disease or condition...." Kathleen tells me no overt statement of intended use is actually required in a 510(k) submission; instead 21 CFR Part 807.87(e) approaches the subject obliquely saying a 510(k) submission should contain "proposed labels, labeling, and advertisements sufficient to describe ... its intended use...." and 807.92(a)(5) mixes concepts asking for "a statement of the intended use...including a general description of the diseases or conditions...." In practice, the reviewer turns to the labeling and interprets your intention.

The Successful 510(k) Janice Hogan, Esq and Yarmela Pavlovic, Esq Listen to Janice Hogan and Yarmela Pavlovic present the whys and hows of crafting a successful 510(k) on CD or OnDemand. Their detailed and thorough presentation covers: 1) the legal framework, 2) finding predicates, 3) chosing the right claim, introducing new features, 4) assessing data requirements, 5) software and combination products, 6) dealing with a not-substantially equivalent (NSE) determination, 7) handling device modifications, and 8) seeing the 510(k) from the reviewers perspective. You'll receive the slide deck, video/audio recording, and links to important guidances. Order here.

The meaning of indications for use is much cleaner: for IVDs it is a description of why a patient would use a certain test; for non-IVDs it is a disease or condition for which a device will be used [21 CFR 814.20(i)]. A statement listing the indications for use must accompany every 510(k) submission.

If you get a 510k for an intended use and then you add a new intended use, you have to file a new 510(k) and demonstrate, newly, that your device is substantially equivalent to a predicate. But if you get a 510k for an intended use and then add a new indication for use, you do not have to demonstrate substantial equivalence newly. So hypothetically you can keep adding new indications for use to an existing device and never file a new 510(k).

But suppose you add indications like "relieves cancer pain", "relieves pain from third-degree burns", or "relieves pain during childbirth"? These statements meet the definition of a new indication, but they also introduce new questions of safety and effectiveness and FDA will expect to see a new 510(k).

Working Group recommendation
The Working Group recommends combining the concepts of "indications for use" and "intended use" and then calling the combined concepts "intended use". They further recommend only certain characteristics be included under the term “intended use” so that modifications that are currently considered to be only changes in “indications for use” are not in the future construed as changes in “intended use”.

CDG comments: Thirty years of device submissions and regulation are built upon the phrases "intended use" and "indications for use". To reshuffle the definitions now will only cause new confusion but could also create a large backlog of additional 510(k)s that would not normally have to be submitted.

An unambiguous definition of "intended use" and exactly how it differs from "indications for use" is what CDG believes is required. For non-IVDs we recommend the term "intended use" be defined to mean the purpose (such as treatment or diagnosis) or function (such as provide support or stabilize) of the device and that the intended use be clearly set forth in the 510(k) rather than rely on a reviewer's interpretation of the labeling. We would like to see an "intended use" statement form like the "indications for use" form included in the 510(k) required documentation.

Currently, a new 510(k) is not required for the addition of a new indication that does not raise new questions of safety or effectiveness. If the terms are combined, will we end with ten times more 510(k) submissions every year? At the present time, we look for a predicate device that has the same intended use and similar indications for use; if the terms are combined, what will constitute a legitimate predicate?

Amend the Act to provide agency with authority to consider off-label use
It has been known to happen that a manufacturer identifies an easy-to-get-cleared intended use for a device, knowing full-well the device will be used for another purpose or even promoting it for that purpose. But it happens we live in a legal society where, although we may contemplate a crime, we aren't guilty until we commit it.

Working Group recommendations
The Working Group recommends seeking an amendment to the Food, Drug, and Cosmetic Act (Act) so that FDA can consider the possibility of off-label use when reviewing a 510(k) and even force the submitter to change the intended use.

CDG Comment: FDA doesn't regulate medical practice (read the Belmont Report), so if a physician uses a device off-label it is between him, his professional society, and his malpractice insurance. And CDRH already has the authority to clear a device as "substantially equivalent with limitations", meaning the labeling has to contain a statement that there is no data for likely unintended uses.

But giving a reviewer the authority to force an intended use on the submitter confuses the roles of reviewer and submitter and pretends the reviewer is a mind-reader. And as a submitter, you may be forced into a regulatory pathway you don't want, or forced into gathering literature or clinical data you can't afford.

Questions of safety or effectiveness
Here are the reviewer's steps toward clearing a 510(k) submission: 1) determine if the device under review has the same intended use as the predicate device, 2) if so, determine the device has the same technological characteristics as the predicate device, 3) if not, determine if the technological differences raise new questions of safety or effectiveness. If there are none, the device is substantially equivalent (SE) to the predicate and the 510(k) is cleared.

Recommendations
The Working Group recommends the agency develop a core list of technological characteristics that, when different, are likely to raise new new questions of safety or effectiveness.

CDG Comment: The recommended core list will be helpful even in the early stages of device design and development. Some of the technologies identified may be addressable in literature reviews, but others may require animal studies or even human studies. The ability of the manufacturer to predict the downstream consequences of a design change will allow them to plan better and design more wisely.

Finding 2: CDRH's current practice allows for the use of some types of predicates that may not be appropriate

One quarter of 510(k) submissions rely on predicates more than five years old
Predicate age is not, in and of itself, a concern. Using an older predicate may be appropriate for mature technologies. But in many cases device performance has improved dramatically and older predicates are widely recognized as substandard. The Working Group felt that submitters sometimes cited poorly performing predicates, including predicates that had been withdrawn from the market.

In 2009, 29% of the predicates cited were devices not registered and listed in FDA's Establishment Registration & Device Listing database. In most cases the predicate itself was cleared through the 510(k) process and was not required to have an independent showing of safety and effectiveness. Because the agency does not have the technological infrastructure to trace a device backwards to arrive at the "original" predicate for the intended use the reviewer is unable to trace the predicate's pedigree.

Recommendation
The Working Group recommends developing a guidance to describe when a device should no longer be available for use as a predicate because of safety and/or effectiveness concerns.

CDG Comment: We disagree that any legally approved device should be unavailable for use as a predicate, even if the device has been recalled or removed from the marketplace. If a manufacturer makes strides in improving the performance of an older device, they should not automatically be restrained from using the original device as a predicate. FDA has the authority to require evidence of safety and effectiveness if that is necessary.

First, FDA should do its part by improving the 510(k) database with features like term explosion, predicate lists, and text search capabilities. For example, yesterday I entered a single keyword into the classification database and got three hits, all for Class III PMA devices, and then I entered same keyword into the 510(k) database and got 16 records. The classification database is clearly flawed. With better research tools at our disposal, we believe the quality of 510(k) submissions will improve on their own.

Rescission authority
The Act is silent with respect to rescission or modification of device clearance, although the Working Group argues that agencies have inherent authority to reconsider their decisions in certain circumstances such as fraud or error, or to rectify their mistakes.

Recommendation
The Working Group recommends that CDRH issue a regulation to define the scope, grounds, and appropriate procedures for partially or fully rescinding a 510(k) clearance.

CDG comment: Clearly, events of the past few years have shown that CDRH should have the ability to rescind 510(k) clearance. In situations where new information comes to light, or errors have been made, it is reasonable for the agency to revoke a decision. What the industry wants and needs is a level playing field that promotes innovation. What the public wants and needs is an agency that makes impartial decisions to protect the public health.

Multiple predicates, split predicates and bundling
First, let's get some definitions straight. You can argue substantial equivalence using two or more predicates for, say, a multi-parameter monitoring system which combines the functions of several devices. For example, you might combine an ECG and a blood pressure monitor into a single device that performs both functions. Another example of multiple-predicate devices are IVD multiplex assay systems, where two or more analytes are assayed in one well. The "Guidance on the CDRH Premarket Notification Review Program 6/30/86 (K86-3)", also known as the Mohan Memorandum, has allowed this use of "multiple predicates" since 1986.

A "split predicate", on the other hand, is a completely different animal. Here, the intended use of a device is based on one predicate and the technological characteristics are based on another. It's like using a lawn mower to trim a hedge.

"Bundling" is yet a different situation. Bundling refers to grouping many devices into a single submission, with one predicate for each separate device. This is a logical approach to save on user fees for a family of devices. Bundling is described in the guidance "Bundling Multiple Devices or Multiple Indications in a Single Submission" and is accepted by FDA when the devices or indications may be addressed in one review.

The chart on the left shows that the more predicates you use in your submission, the longer the review time. This is logical because the reviewer is compelled to assess the scientific issues associated with each predicate mentioned.

The agency's problem is that it does not have an adequate database to trace the predicates backwards over a number of submissions. They are forced to manually review the text of each 510(k) submission to asses its predicates.

Recommendation
The Working Group recommends the agency develop a guidance describing when multiple predicates are appropriate, disallowing the use of split predicates, and updating its existing bundling guidance to distinguish between multiplex devices and bundled submissions.

CDG Comment: we agree the guidance is necessary and that using multiple predicates makes sense for two or more products combined into one or for multiplex IVD assays; and we agree that bundling predicates makes clear sense for families of similar devices. Furthermore, CDG believes that using split predicates—one for the intended use and one for technological characteristics—is acceptable when accompanied by new data to support safety and effectiveness.

Updated and expanded guidance documents are welcome because they make they make planning regulatory strategies easier and review processes more efficient.

CDG can help write your next 510(k)
Kathleen Johnson is an independent monitor and regulatory consultant for non-IVD medical devices. Gail Radcliffe is an independent regulatory and clinical expert for IVD devices. Both are part of a family of technical professionals who work with CDG, many with 10-15 years experience in their field. CDG has capabilities in in-vivo diagnostic, in-vitro diagnostic, and non-diagnostic medical devices; regulatory engineers; a toxicologist experienced in device biological safety; statisticians; and other professionals who may contribute to 510(k) preparation or clinical trial implementation. We work collaboratively with a point-person on your side so that you are involved in the process every step of the way.

Contact us
Phone or email us at 773-489-5721 or [email protected].

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

 

CDRH's 510(k) Working Group Preliminary Report

TAKE THE 510(K) REVIEWER SURVEY
A Cycle of Whitepapers by Nancy J Stark and Kathleen Johnson

It's been a long time coming, with complaints dating back for several years, but FDA's problems really became public when a group of FDA scientists and physicians wrote to John Podesta, head of then President-elect Barack Obama's Transition Team that "America urgently needs change at FDA because FDA is fundamentally broken...the scientific review process for medical devices...has been corrupted and distorted by current FDA managers...." The open letter was particularly significant because it was copied to six senators and four congressman and published in the national press and on every blog on the internet concerned with medical devices.

It was followed by a host of General Accounting Office (GAO) reports, the resignation of Center Director Daniel Schultz and Office of Device Evaluation Director Donna-Bea Tillman, and initiation of an Institute of Medicine (IOM) review of the 510(k) process due out in 2011.

 
Internal Assessment at CDRH
Meanwhile, the Center itself initiated a series of activities to assess the 510(k) process by establishing a 510(k) Working Group and a Task Force on Utilization of Science in Regulatory Decision Making. The Working Group and Task Force published preliminary reports in August 2010.

The working group, comprised of representatives from across CDRH, was assigned to develop an understanding of the way the 510(k) process currently functioned, the perspectives of CDRH staff and a range of external constituencies on the program, and potential areas for improvement.

As part of its research, the Working Group co-hosted a public town hall meeting called "Strengthening CDRH and the 510(k) Process" on 18 February 2010 in conjunction with the Task Force on the Utilization of Science in Regulatory Decision Making. A CD of the public meeting is available at Strengthening the Center.

510(k) Survey
To assess the consistency of CDRH reviewers’ interpretation and understanding of 510(k) regulations, guidance documents, and review practices, the Working Group conducted a survey of the Center’s premarket reviewers and managers. The survey consisted of twenty questions related to reviewers’ and managers’ knowledge and opinions on a range of areas of concern.

Reviewer Cohort. The survey was sent by email to all reviewers in CDRH’s two premarket review offices, the Office of Device Evaluation (ODE) and the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD). All reviewers were strongly encouraged to complete it. Out of a total of 308 reviewers, 215 reviewers took the survey, and at least 162 respondents answered each question.

Manager Cohort. Premarket review managers also completed the survey as a separate cohort of respondents. Out of a total of 38 managers (Branch Chiefs, Deputy Division Directors, and Division Directors) in ODE and OIVD, 21 ODE Branch Chiefs and Deputy Division Directors took the survey, and at least 13 respondents answered each question.

Take the Survey Yourself
We've put the Working Group survey into SurveyMonkey so that you can take the it yourself, benchmark your answers against your colleagues', and then compare your answers to Center staff. It's useful and information to see if your understanding of the 510(k) clearance process is the same as the agency's. Click on survey to take the test, click on benchmark to compare your answers to your colleagues, and then Center Reviewers to see the agency's responses.

When you've finished, submit the form at the end of the survey to receive your OnDemand access to "Surviving Medical Device Recalls" presented by the Center's Bioresearch Monitoring staff.

When you need to write a 510(k), CDG has people who can help
CDG has a family of technical professionals, each with 10-15 years experience in medical devices and eager to help you write your 510(k). We have regulatory professionals for in-vivo diagnostic, in-vitro diagnostic, and non-diagnostic medical devices; regulatory engineers; a toxicologist experienced in device biological safety; statisticians; and other professionals who can contribute to 510(k) preparation. We work collaboratively with a point-person on your side so that you are involved in the process every step of the way. View our company brochure and capabilities sheet.

Contact us
Phone or email us at 773-489-5721 or [email protected].

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

 

 

Good Monitoring Practices

GLOBAL CONSENSUS
A Whitepaper by Nancy J Stark, PhD

It may be a coincidence, but it seems to me that the device industry emerged from a long sleep after the August 31, 2010 CDRH Webinar on Preliminary Internal Evaluations of the 510(k) process. The webinar entertained questions from the audience regarding two preliminary reports published by: 1) the 510(k) Working Group, and 2) the Task Force on Utilization of Science in the Regulatory Decision-Making Process. Both groups were comprised of representatives from across CDRH to assess the challenges faced by Center management and staff in the 510(k) process and to assess how effectively science is used to evaluate 510(k)s.

One recommendation of the 510(k) Working Group was to "define the term 'clinical data' in order to foster a common knowledge among review staff and manufacturers about what constitutes 'clinical data' ". Recommendations by the Task Force on...Science... were to "continue to engage in the development of...international consensus standards, which, when recognized by FDA, could help establish basic guidelines for clinical trial design, performance, and reporting," and for the Center "to expand its ongoing efforts related to clinical trials...to include clinical trials that support 510(k)s". Possibly the most significant and repeated recommendation made in the reports was to improve the overall quality of clinical trials.

Good monitoring is essential
Think about what happens in a clinical trial. A manufacturer located in one state or country contracts with an investigator in another state or country to conduct a clinical trial that may last from a month to as long as several years. Like all human beings, investigators lose interest in the trial, deviate from the protocol to experiment with their own ideas, enroll subjects in competing studies, or generally misbehave, without regular eyeball contact from the sponsor.

Monitoring is the mechanism by which a sponsor remains engaged with an investigator. Monitors are the individuals charged with maintaining that eyeball contact.

Types of monitoring visits
Clinical trials are implemented in 'project management' phases of prestudy design, study initiation, implementation (duration) and close-out. Monitoring activities are often designed to parallel the process of the clinical trial. While the transition from one phase to another is not carved in stone, I've tried to describe transition points that are commonly used and easy to conceptualize.

 

Prestudy 'visits'
Pre-investigation or assessment visits are intended to select investigators and prepare sites for the study. They are better perceived as a process in which the capabilities and business relationship of the sponsor and investigator are established.

Both FDA and ISO envision this as a time for sponsors to assure that investigators understand the investigational nature of the device, the requirement to wait for IRB approval, the need for informed consent, agreement that records will be created and made available for monitoring, and that contractual obligations are mutually understood and agreed to. This is also the time during which budget agreements and financial arrangements are made between sponsor and site. The period of time may take several months, visits, phone calls, and email messages and can be thought of as spanning from project conception to first subject consented.

Initiation visits

The main focus of the initiation process is investigator and study staff training. Training may begin with an investigator's meeting if there are many investigators involved in the study. Or investigative sites may be trained one at a time and may include practice on simulated patients or live animals. The importance of training the investigator to device use cannot be over-emphasized. Even investigators familiar with your type of device will need to review special features, materials, software, hardware, instructions for use, and protocol requirements. Misuse of an investigational device by an investigator may come back on the sponsor as a failure to adequately train the user and may be considered an adverse event.

During this phase the monitor will set up record-keeping systems by building Investigator Regulatory Binders, Coordinator's Study Manuals, Subject Binders, Source Document Verification Logs and sponsor files.

It is a common practice for subjects to be consented but not considered enrolled in a study until they have passed subsequent screening procedures and been exposed to the device. But the practice of viewing consent and enrollment as separate events is now frowned on by FDA. They are concerned that subjects may be consented, and then dropped from the study without documentation about why. The preferred viewpoint is that consent and enrollment take place at the same moment. Then if a subject later fails screening, the reasons are documented and the subject is exited from the study. Study initiation culminates when the first device is placed on the first subject.

Routine monitoring visits
A routine monitoring visit is an on-site visit in which the monitor observes the process of the study, compliance to protocol, compliance to regulations, completeness of documentation, and verifies accuracy of data on the case report forms against source information. Case report forms should be verified for accuracy, logic, completeness, legibility, and contemporaneousness; electronic forms should be checked for traceability (i.e., who filled out the screen.) Monitoring should take place on a periodic basis, but I suggest you allow no more than 2-3 days of work to accumulate at a site.

Monitoring requires an extensive skill set. It requires an intimate knowledge of clinical regulations and company procedures, knowledge of the device function and possible malfunctions, knowledge of the disease or condition being studied, the ability to solve problems and work independently, and the ability to write a comprehensive and lucid report that captures the progress of the study and action items for the future.

Monitoring Reports >> Action Item Database >> Open Action-Item Checklist

Monitors need a special kind of personality. They should be people who can work with busy sites, who love data, who can sift through pieces of information and fit them together, who do not leave details unaddressed, and who cannot tolerate an unbalanced checkbook.

Off-site monitoring
Off-site monitoring is an alternative to travel when a site is known as well-organized. Data can be transmitted by fax, pdf, or electronic means and checked for everything but accuracy to source files.

Close-out visits
Close-out visits deal with ending issues and have the goal of making the site inspection-ready. All open action items are addressed, open queries resolved, and reports filed. Close-out visits are like filing income taxes, if you've done a good job of record-keeping all year long the close-out visit will go quickly; if not, it could take days.

If you liked the whitepaper, take the workshop
If you liked this whitepaper, then take the workshop. The learning objective is to review the skills of monitoring in order to help assure quality in clinical trials. This is an intermediate level course, participants are expected to have a basic knowledge of clinical research and device regulations. Sign up here or phone us at 773-489-5706.

A quiz, of course
The five-hour workshop is following by a half-hour online quiz, taken on your own time within the following two weeks. The quiz is designed to test your learning of the concepts discussed in the lecture and your ability to apply those concepts to real-life issues.

You will receive, we will discuss
[x] Printable PowerPoint slides.
[x] Clear example distinguishing intended use, indications, claims and warning.
[x] Monitoring procedures and templates.
[x] Recent monitoring warning letters.
[x] A graded quiz with immediate test results.
[x] One computer connection for one learner (each learner must log-in individually).
[x] Certificate of Attendance and 0.55 CEUs.
[x] A copy of the CRA Handbook 2010 (electronic) with registration by October 13, 2010.

Who should attend
[x] Monitors.
[x] Clinical research associates.
[x] Managers and directors of clinical research.
[x] Start-up companies planning their first clinical trial.

Presenter
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration
The 5 hour workshop will be presented on Wednesday, 20 October 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Or you can take the event later by CD or OnDemand. Sign up at here or phone us at 773-489-5706.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Introduction to Medical Device Regulation: US

The fundamentals of US Regulations are unlikely to change...

A Whitepaper and Workshop by Nancy J Stark, PhD
Tuesday 6 July 2010, 10:00 AM Central; or on CD.

In this whitepaper I want to discuss the fundamentals of medical device regulations in the United States with the goal of determining whether or not a clinical study is necessary in order to obtain FDA clearance. This is an introductory discussion intended for those who are new to the medical device industry.

The fundamentals of medical device regulations in the European Union are discussed in a companion whitepaper and workshop. The companion EU workshop is available Thursday, 1 July 2010, 11 AM Central and on CD.

Food, Drug and Cosmetic Act
In the States, medical devices are regulated by the Food, Drug and Cosmetic Act. Then called the Food and Drug Act, it was the first piece of legislation to result from investigative journalism, namely a novel titled "The Jungle" by Upton Sinclair. Sinclair described the filthy conditions of pre-WWI Chicago stockyards and the contamination of our food supply. You can still buy the book, a heart-wrenching, stomach-punching period piece, for $5.95. Sinclair published The Jungle in 1906, and the Food and Drug Act was passed in 1923. In 1933, as part of the 'New Deal', legislation was introduced to expand the Act to cover medical devices; the expansion passed in 1938.

Adulteration and Misbranding
The Food and Drug Act set forth two simple concepts that still govern medical devices today—adulteration and misbranding. Adulteration speaks to the issue of filth, contamination, or toxins being present in or on a medical device. For example, some devices use water during the manufacturing process. The water must be pyrogen free or the finished device will probably be contaminated with pyrogenic material. Pyrogens cause an intense fever spike when they get into the body—an unwanted medical occurrence for any device.

Misbranding speaks to the issue of making false or misleading statements. For example, if I say the device can be used to reduce an HIV viral load, but it not cleared for this indication, it is misbranded. If I say it is sharp enough for a surgical cut and it isn't, it is misbranded.

If I say the knife is sterile, and it isn't, it is both adulterated and misbranded.

Chapter V: Drugs and Devices
Chapter V of the Act deals with drugs and devices. This is where you find the relevant sections of the Act, itself. Follow the link to Chapter V if you want to read more about any of the topics.

Regulations
If you look at the Act, you'll see that it is general; written to last over time and lacking in the specifics that enable day-to-day implementation. The specifics are left to the regulations, which are promulgated by the Food and Drug Agency (FDA). Regulations are rules which have the force of law. They are first published as proposed rules and are open to public comment. Some comments are accepted, other rejected. When the regulation is first published as a final rule it appears in the Federal Register along with a summary of the comments and FDA's responses and explanations, called the preamble. Preamble's have legal standing and are worth your while to read and understand.

Once a year the regulations and associated amendments, but not the preambles, are published in the Code of Federal Regulations, Title 21. 21 CFR, Parts 1-99 are regulations that apply to devices, drugs, and biologics. Parts 800-1299 are regulations that apply only to devices. If you work in clinical research, you should become intimate with Parts 50, 54, 56, 812, and 814.

Device Classification—point of entry
Devices are as diverse as toothbrushes to heart valves, or sunlamps to breast implants. It would be unreasonable to regulate all devices the same way. Wrapping your mind around a country's approach to device regulation is challenging. The point of entry is to first learn how that country classifies devices. All countries classify devices by history or risk, and then regulate the devices differently depending on its classification. In the States, devices are classified as Class I—General Controls, Class II—Special Controls, and Class III—Premarket Approval.

Class I devices have a reasonable assurance of safety and effectiveness if manufactured under current good manufacturing practices. Approximately 74% of the Class I devices are exempt from the premarket notification process (i.e., 510k clearance). These exemptions are listed in the classification regulations of 21 CFR and have been collected together in the Medical Device Exemptions document.

Class II devices have a reasonable assurance of safety and effectiveness if manufactured under current good manufacturing practices and whatever special controls deemed necessary by FDA, such as performance standards, postmarket surveillance, patient registries, guidance documents, or evidence of efficacy from a well-controlled clinical study.

Class III devices are devices purported or represented to be for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health and there is not sufficient information to establish a performance standard for reasonable assurance of safety and effectiveness.

Intended Use, Indications for Use
Let's say you are developing a device that is new to your company. Your first concern is to identify its classification, because all other regulatory requirements will stem from there. But the classification will depend on a few more variables you'll have to fix before you can make that determination.

Intended Use
The first decision is to decide on the intended use for the device. In a market-driven company we probably have an indication (customer need) looking for a device, but in technology-driven companies it is common to have a device looking for an intended use. Think in terms of an active verb: do you intend to ablate tissue, vibrate cells, stimulate neurons, fix body parts, take images, or measure impedance? Deciding on your intended use for a device is the first step in determining its classification.

Indication for use
The next step is to decide on the disease or condition you plan to diagnose, cure, mitigate, treat, or prevent. Think in terms of diseases and conditions to which the intended use can be applied. You might ablate tissue in order to prevent tumor growth, you might vibrate cells in order to intercept a seizure, you might fix the spine in order to prevent curvature or treat scoliosis, and so on. The intended use may have many applications in medicine, i.e., there may be many diseases or conditions to which it can be applied.

Some indications will cause your device to be classified higher than other indications. For example, if you say your device will diagnose breast cancer it is going to be a Class III device, but if you say it is a adjunct test for the diagnosis of breast cancer it will be a Class II device. If you indicate a device that exposes to body to magnetic waves as a treatment for HIV it is going to be a Class III device, but if you indicate that magnetic waves help activate the immune system to viral load, it may be a Class II de novo.

Think of your device as consisting of two parts: 1) the physical device, and 2) its indications for use. If you are a start-up firm, choose an indication for use for which it is easy and inexpensive to get FDA clearance. Go after the harder, and more profitable, indications for use after you have experience and cash flow.

How to determine classification
Go to FDA's product classification database and search for a part of the device name or, if you know the device panel (medical specialty) to which your device belongs, go directly to the listing for that panel and identify your device and the corresponding regulation.

It may sound simple to find your device, but it isn't. The classification database does not have a fuzzy search engine; you will find only what you ask for. Suppose you have a radio-frequency ablation device. A search for "radio frequency ablation" turns up nothing, a search for "RF ablation" turns up nothing, finally a search for "ablation" brings up twelve records: one is a mapping instrument to plan the ablation, four are for cardiac atrial flutter, one is for endometrial ablation, one for urological ablation, one—for treatment of varicose veins—is grandfathered in as a pre-amendment device, two are low-energy devices for general soft tissue ablation, one uses ultrasound as a high energy source, and one uses liquid nitrogen for cosmetic surgery (like removing moles).

It is useful to note is that the primary tissue (think disease or condition) being ablated dictates which device panel reviews the device, and the energy intensity (high or low) as well as the newness of the technology dictates its classification. Unfortunately, we still don't know how our RF-ablation device is classified.

Device classification panels
FDA has classified and described over 1,700 distinct types of devices and organized them in the CFR into 16 medical specialty "panels". For each of the devices classified by the FDA the CFR gives a general description including the intended use, the class to which the device belongs (i.e., Class I, II, or III), and information about marketing requirements. Your device will presumably meet the definition in a classification regulation contained in 21 CFR 862-892.

A search for "RF" in the product classification database is more useful. We find seven devices, one is a Class III device for RF/microwave hyperthermia for cancer treatment—sounds like a good match and finally we know the class and regulatory status of our device and indication.

Let's discuss the product code. The product code, together with the product name, uniquely identifies a category of devices for FDA and is a useful way to find related products. If you go to the PMA database and search on the product code LOC, you will find 27 PMA submissions or amendments. Here you will find some useful information, such as the manufacturer of the devices, when they received clearance, location of the manufacturing facilities, which advisory panel reviewed the PMA, and more.

Notice the absence of a Regulation Number? While FDA may say: "Your device should meet the definition in a classification regulation contained in 21 CFR 862-892," the truth is that it can take years before FDA assigns a regulation number to a new product category.

510(k) or PMA
The point of classification is to determine the pathway to FDA clearance. You don't have a choice in the matter, unless you want to revise the indications for use. To summarize it simply:
[ ] Class I—74% are exempt from requiring FDA clearance, the remainder need a 510(k).
[ ] Class II—requires a 510(k), which is a type of FDA submission in which you argue that your device is substantially equivalent to another device which was on the market prior to May 28, 1976.
[ ] Class II de novo 510(k)—a Class III device that is a new technology of low risk; for example exposing the hands to a magnetic field for immune system stimulation. New technologies are automatically Class III devices, but the manufacturer can petition FDA for a down-classification to Class II. The difference is the 510(k) requires de novo (from the beginning) evidence of safety and effectiveness, rather than evidence of substantial equivalence, because there is nothing to be equivalent to.
[ ] Class III—requires pre-market approval (PMA).

The BIG question—do you need a clinical trial?
The question we've been trying to answer with all of this is whether or not we need to do a clinical trial in order to get FDA clearance. The answer is:
[ ] No, if you have a Class I device.
[ ] Maybe, if you have a Class II device. About 10% of 510(k)s require clinical trials in order to support the argument of substantial equivalence.
[ ] Yes, if you have a Class II de novo device.
[ ] Yes, if you have a Class III, PMA device.

If you liked the whitepaper, take the workshop
The objective of the workshop is to learn the basics of FDA device regulations and how to determine if you need a clinical study in order to get FDA clearance. Sign up at registration.

This is an introductory workshop and focuses on US regulations. A complimentary workshop focusing on European regulations is also available.

You will receive, we wil discuss
[x] PowerPoint slides.
[x] A three-hour presentation.
[x] Discussion of the types of 510(k).
[x] Difference between 510(k)s and PMAs.
[x] How to take advantage of the Mohan memorandum.
[x] Distinction between guidance documents and standards.
[x] Supporting handouts, flowcharts, and graphic presentations.
[x] A complimentary US/ISO Adverse Event mousepad/notepad (by mail).
[x] A 30-minute quiz to reinforce your learning experience.
[x] CEUs and certificate of attendance.

Who should attend
[x] Anyone new to medical devices.
[x] Anyone new to medical device clinical trials.
[x] Anyone needing to know about medical device regulations.

Presenter
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.

System requirements
[x] Personal computer.
[x] Internet Access.
[x] Telephone.

Date, time, registration for US Workshop
The three-hour workshop will be presented on Tuesday, 06 July 2010, at 10:00 Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Date, time, registration for EU Workshop
The three-hour workshop will be presented on Wednesday, 1 July 2010, at 1:00 pm Central Time. Event materials will be distributed the day before the workshop. Sign up at registration.

Learn the world discount
Register for both workshops and get $100 off! Enter the coupon code SUMMER at check-out.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc