Introduction to Medical Device Regulation in the US

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

A Whitepaper and Workshop by Nancy J Stark, PhD
Tuesday, 06 July 2010, 10 am Central; or OnDemand soon after.
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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 OnDemand soon after.

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, 6 July 2010, at 10:00 am 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 11:00 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