1. Team SaltronTM October 25th, 2010
Food and Drug Administration
Team SaltronTM
October 25th, 2010

2. An Overview of the FDA Regulates $1 trillion worth of products
25 cents of every dollar spent by Americans
Regulates cosmetics, food, blood supply, medicines, biological, medical devices, radiation-emitting products, and feed & drugs for animals
Performs surveillance of regulated products
Makes sure products are labeled truthfully
Employs 9,000 employees
cost is $3 / person/yr
95,000 FDA-regulated businesses

3. An Overview of the FDA (cont)
Visits to 15,000 facilities/yr
collect 80,000 domestic & imported product samples
Violations of FDA laws & regulations
encourage firm to voluntarily correct the problem
recall a faulty product from the market
about 3,000 products recalled/yr
FDA can go to court to force a company to stop selling a product, can seize and destroy products
Also criminal penalties against manufacturers and distributors

4. Example of Product Recall
2010 Infant Formula Recall
On September 22, 2010, Abbott  issued a voluntary recall of certain Similac powdered infant formula after identifying a common warehouse beetle (both larvae and adults) in the finished product at their Sturgis, Michigan plant.
The company said it was voluntarily recalling just shy of 5 million units of Similac, the top-selling baby formula, in United States, Guam, Puerto Rico and other Caribbean markets.

5. Major Centers at FDA
FDA is an agency of the Public Health Service which is part of the Department of Health and Human Services
Center for Biologics Evaluation & Research
regulates biologically produced products such as blood, vaccines, biological therapeutics
Center for Drug Evaluation and Research
regulates the safe and effective use of drugs
Center for Devices and Radiological Health
regulates the safe and effective use of medical devices and eliminates unnecessary exposure to man-made radiation from medical, occupational, and consumer products

6. Latest Major Medical Device Law
The Medical Device User Fee and Stabilization Act (MDUFSA) of 2005.
The MDUFSA amends the user-fee system created by the original Medical Device User Fee and Modernization Act of 2002, which allows the FDA to charge a fee for medical device product reviews.

7. History of the FDA
Federal Food, Drug, and Cosmetic Act (FD&C Act) 1938
US Congress for the first time addressed issues related to medical devices and drugs
Radiation Control & Health Safety Act of 1968
both medical and nonmedical applications
performance standards for x-ray systems, computed tomography, laser-based devices, and ultrasonic diagnostic and therapeutic products
Cooper Committee Report 1970
requires premarket clearance of risky devices
based on 10,000 device-related injuries over a 10 yr period
classified medical devices into 3 groups: Class I, Class II, Class III
Numerous deaths from a popular consumer medicine (elixir of sulfanilamide) in the 1930s led Congress to enact the FDCA in The FDCA significantly expanded federal regulatory authority, most notably by requiring premarket safety approval for new drugs, adding cosmetics to the statutory scheme, and providing express authority for factory inspections.
General Electric’s 1967 recall of 90,000 television sets believed to emit dangerous
levels of radiation. Congress soon proposed a federal radiation control bill.

8. History of the FDA (cont)
Bureau of Medical Devices (BMD) 1974
began classifying medical devices
created Office of Small Manufacturers Assistance to help manufacturers understand the law
Medical Device Amendments 1976
made into law the tripartite medical device classification scheme
manufacturers had to notify FDA prior to marketing any device, unless the device was exempt
introduced concept of substantial equivalence to pre-amendment devices
certain products previously classified as drugs were reclassified as class III devices
required registration of medical device establishments
authorized what became Good Manufacturing Practices (GMP)
expanded FDA enforcement authority
Medical Device Amendments Very similar to copper committee report although it includes more enforcement authority of FDA. It classifies the medical devices into the three classes.
Class III are required to contact the FDA prior to marketing device.
Any device that is equivalent to devices prior to 1976 can market immediately.

9. History of the FDA (cont)
Good Manufacturing Practices Regulation (GMP) 1978
comprehensive set of requirements on
facilities
methods
controls for manufacturing, packaging, and storage of medical devices
Medical Device Reporting Regulation (MDR rule) 1984
requires manufacturer to submit a report to FDA whenever a device they marketed might have caused an adverse event resulting in death or serious injury
must file a report whenever 1 device was known to have failed and a repeat occurrence would be likely to lead to death or serious injury
Good Manufacturing Practice (GMP) regulations also were authorized at that time. These are a set of procedures to ensure that devices are manufactured to be safe and effective through quality design, manufacture, labeling, testing, storage, and distribution.

10. History of the FDA (cont)
FDA Plan of Action (first) 1985
response to criticism of FDA’s implementation of the amendments
maintain regulatory control without putting up roadblocks to innovation
provided guidelines for functional substantial equivalence rather than technological equivalence
allowed premarket notifications (PMN or 510 (k) s) rather than premarket approvals (PMA)
FDA Plan of Action (second) 1987
FDA would focus on risk assessment for informed judgments on device safety
emphasize post-market surveillance of devices
FDA focus on user education
A 510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and effective, that is, substantially equivalent, to a legally marketed device (21 CFR (a)(3)) that is not subject to PMA.
device is substantially equivalent if, in comparison to a predicate it:
has the same intended use as the predicate; and
has the same technological characteristics as the predicate; or
has different technological characteristics and the information submitted to FDA;
does not raise new questions of safety and effectiveness; and
demonstrates that the device is at least as safe and effective as the legally marketed device.

11. History of the FDA (cont)
FDA reviewer Guidance for Computer-controlled Medical Devices undergoing 510(k) review 1991
applies to medical products having software as part of the device
ensures uniform review of such devices
FDA Regulatory Procedures Manual Revision 1991
replaced older enforcement system of notices of adverse findings and regulatory letters
now a single type of FDA communication - warning letter
Medical Device Amendments of 1992
refined medical device tracking regulations
made noncompliance with postmarket surveillance a civil or criminal penalty
FDA can require repair, replacement, or refund for devices not designed or made properly

12. History of the FDA (cont)
Temple Report 1993
found deficiencies in the design, conduct, and analysis of clinical trials in support of PMA’s and 510(k)’s
expressed a need for better scientific rigor, called for controlled, randomized, and masked trials when feasible
Medical Device Reporting regulation for Manufacturers 1995
requires device manufacturers to provide FDA with more information about adverse events with substantially more specificity
Revised GMP Regulation 1996
FDA rules for GMP now include preproduction quality control

13. History of the FDA (cont)
FDA Modernization Act of 1997
device industry’s efforts to reform FDA
their view, FDA is inefficient, unfair, needs reform
became effective February 19, 1998

14. Important Definitions
Medical device (section 201 of the Federal F,D, & C Act)
instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article including any component, part, or accessory which is:
recognized in the official National Formulary, or the United States Pharmacopeia (USP), or any supplement to them;
intended for the use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or animals; or
intended to affect the structure of any function of the body of man or other animals; and which does not achieve its primary intended purposes through chemical action within or on the body of man… and which is not dependent upon being metabolized for the achievement of its primary purposes (i.e. not a drug).

15. Classification of Medical Devices
Class I Medical Devices
not life sustaining, no risk to life
least risk of injury to either the operator or the patient
only general controls such as adulteration/misbranding, registration and listing, repair, replacement, refund, and banned products are needed to ensure safety and effectiveness
examples include manual stethoscopes, surgical scalpels, forceps, wheelchairs, elastic bandages, exam gloves
some class I devices can be exempt from PMN and/or GMP

16. Classification of Medical Devices
Class II Medical Devices
also not life sustaining
need additional controls such as performance standards, postmarket surveillance, special labeling, patient registries, guidelines, recommendations
examples include endoscopes for viewing body cavities, surgical lasers, powered wheelchairs, infusion pumps, surgical drapes
usually exempt from proving safety and efficacy, however FDA may require additional laboratory or clinical studies
class II devices are never exempt from PMN or GMP

17. Classification of Medical Devices
Class III Medical Devices
general and special controls not sufficient to establish safety and efficacy
used to support or sustain life or present a potential unreasonable risk of injury or illness
generally requires an approved premarket approval (PMA) application (PMAA), unless:
equivalent to devices marketed before 5/28/76 in which case you follow a premarket notification (PMN or 510(k)) process unless FDA has already made that type of device follow the PMA process
PMA can take several years
Failure mode analysis, animal tests, toxicology, human clinical trials (IDE and IRB) are required
examples include indwelling gas analyzers, implanted cardiac pacemakers, balloon catheters, stents, cardiac arrhythmia alarms, heart valves, breast implants

18. Types of Devices In Vitro Diagnostics
Medical devices that test for diseases, conditions, or infections.
Can be used in a laboratory setting, a professional healthcare setting, or even for at home use.
Includes reagents, instruments, kits, or systems used to examine body specimens such as blood or tissue.
Examples:
Common tests include blood tests for glucose, liver enzymes, levels of electrolytes such as calcium, sodium, and potassium, and tests for drugs.
‘Specimen receptacles’ - devices specifically intended by their manufacturers for the primary containment and preservation of specimens derived from the human body for the purpose of in vitro diagnostic examination.
Exempt: General lab equipment not specifically
intended for in vitro diagnostic examination.

19. Types of Devices (cont)
Combination Devices
A product that is a combination of a drug, device, and/or biologic.
Includes products that are physically or chemically combined, products that are packaged together as one unit, and any other products that are intended for use specifically with another product.
Office of Combination Products (OCP) assigns which center has the primary responsibility for these types of devices.
Examples:
Device coated with
drug or biologic
Drug delivery
system

20. Types of Devices (cont)
Custom Devices
Devices ordered by a physician or dentist for his or her own use or for a specific patient and that are not generally available.
These devices cannot be labeled or advertised for commercial distribution.
Example: Zimmer Custom Products!!!

21. Types of Class III Devices
Preamendment Device
Device that was in commercial distribution before May 28, 1976, the date the Medical Device Amendments were signed into law.
Require a PMA only after FDA publishes a regulation calling for PMA submissions.
Postamendment Devices
Device that was first distributed commercially on or after May 28, Subject to same requirements as equivalent preamendment devices.
Transitional Devices
Device that was regulated as a new drug before May 28, 1976.
Any Class III device that was approved by a New Drug Application (NDA) is now governed by the PMA regulations.
Some of the transitional devices were down-classified to Class II.

22. What’s the Difference!? Medical Device Manufacturer
Any person who manufactures, fabricates, assembles, or processes a finished device, including any repacker and/or relabeler.
Medical Device Distributor
Any person who furthers the marketing of a device from the original place of manufacture, whether domestic or imported, to the person who makes final delivery or sale to the ultimate consumer or user, but who does not repackage or otherwise change the container, wrapper, or labeling of the device or the device package.
Medical Device Company Owner/Operator
The name of the corporation, subsidiary, affiliated company, partnership, or proprietor.

23. Important Definitions
Registration
Medical device manufacturers, US importers, distributors, repackers, and relabelers must register with the FDA.
Exempt from registration:
Licensed practitioners such as physicians, dentists, and optometrists who manufacture or alter devices solely for their own use or practice.
Retail outlets, research manufacturers with no commercial products, warehouse operators provided they do not alter the devices, delivery people, people who dispense such as audiologists, optometrists, etc.

24. Important Definitions (cont)
Device Listing
After being cleared for commercial distribution, the owner/operator must list the device with the FDA.
Identifies the owner/operator and all others involved in the manufacturing, repacking, relabeling, specification development, distribution, or importation of the device.

25. Important Definitions (cont)
Device Labeling
FDA requires following information on a label:
Common name of device and accurate statement of its principal intended actions.
Adequate directions for use:
Indications, dose, frequency of administration, duration of administration, time of administration, route of administration, preparation for use
Declaration of its net quantity of contents.
Name and address of the manufacturer, packer, or distributor.

26. Important Definitions (cont)
Premarket Approval (PMA)
PMA is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices.
PMA’s must contain sufficient scientific evidence to ensure it is safe and effective for its intended use.
FDA regulations provide 180 days to review the PMA and must decide that the device is safe and effective for PMA approval which may use advisory committees
If there is not an effective date listed for the PMA then a Class III 510(k) should be submitted.

27. Important Definitions (cont)
Premarket notification (PMN or 510(k) )
Any Class I, II or III device intended for human use that does not require a PMA must submit a 510(k) unless:
the device is exempt from PMN
was marketed before May 28, 1976
requires premarket approval (PMA)
This is a premarket submission to the FDA that demonstrates that the device is as safe and effective as a legally marketed device which is not subject to PMA (aka equal).
The legally marketed device to which equivalence is drawn is known as the predicate device.
This allows the FDA to decide whether the device is substantially equivalent to a legally marketed Class I or Class II device, or to a predicate Class III device not requiring a PMA

28. Important Definitions (cont)
Premarket notification (PMN or 510(k) ) (cont)
To say the device is substantially equivalent means it need to be AT LEAST as safe and effective as the predicate device therefore it:
Has the same intended use as the predicate and as the same technological characteristics as the predicate OR
Has the same intended use as the predicate and has different technological characteristics and information submitted to the FDA
A device may not be marketed until the device is declared substantially equivalent. If it is not then the submitter may
Resubmit a 510(k) with new data
Submit a PMA
Or reclassify the device

29. Important Definitions (cont)
Good Manufacturing Practices (GMP)
Part of a quality system covering the manufacture and testing of pharmaceuticals, food and medical devices.
Includes clearly defined and controlled processes to validate a process for consistent testing and results.
Must provide assurance that the device is manufactured under regulated conditions and controls that ensure it is safe and effective for the intended use.
Needs a quality assurance program (QA)
Refers to a program with systematic monitoring and evaluation to ensure the quality of the system/product is met.

30. Important Definitions (cont)
Investigational Device Exemptions (IDE)
Section 520 of the FD&C Act provides manufacturers the authority to ship devices solely for investigational use if they obtain approval for an IDE as part of a Pre Market Approval
get the clinical data needed for the PMA
Unless exempt, all clinical evaluations of investigational devices must have an approved IDE before starting the study.
If evaluation is not cleared for marketing requires:
An IDE approved by an institutional review board (IRB) and if there is a risk with the device then FDA approval is also needed.
Consent from patients
Labeling for investigational use only
Monitoring of the study as well as records and reports.

31. Important Definitions (cont)
Investigational Device Exemptions (IDE) (cont)
the IDE application must include
device description
prior investigations
investigational plan
facility where the device was made
investigator agreements
institutions where the study will be conducted
proposed labeling
description of clinical evaluation and IRB supervision
informed consent from human subjects

32. Example in Industry
New Development Product (i.e. at DePuy Orthopaedics)
Once there is a production level device it must pass certain standards and the data is submitted to the FDA for review.
For example: Fatigue testing is set up according to regulations given by the FDA for standard hip implants of a certain size/length.
Each test is set up with enough samples to provide consistency, say at least 8 samples NEED to pass to validate the product.
Strict protocols are followed to ensure that each requirement is met and then the parts are fatigued at a desired load for a certain number of cycles (say 5 million).
Assuming all parts passed the fatigue testing, the protocols along with the testing reports are submitted to the FDA for approval.
Though it may seem like a simple process, the development of a new product from start to finish can and will take years to complete and the FDA approval process is crucial for launching said product on time.