Food and Drug Administration

Michael Jordan and Jeff BeegleOctober 23nd, 2013

An Overview of the FDA

Regulates more than $1 trillion worth consumer goods. 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

95,000 FDA-regulated businesses

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

Example of Product Recall

OASYS Midline Occiput Plate On May 30, 2013, Stryker issued an Urgent

Medical Device Recall requesting medical facilities to examine their inventory and immediately stop distributing or using the recalled lots.

Stryker has received reports indicating post-operative fracture of the pin that connects the tulip head to the plate body. This may cause serious adverse health consequences including blood loss, nerve injury, and the need for revision surgery to replace the fractured implant.

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

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.

The History of the FDA

History of the FDA

Oldest comprehensive consumer protection agency in the U. S. federal government

Appointment of Lewis Caleb Beck to the US Patent Office in 1848 Job of carrying out chemical analysis of

agricultural products 1906 Pure Food and Drugs Act (The Jungle) Began as Division of Chemistry, then the

Bureau of Chemistry, then the Food, Drug, and Insecticide Administration (1927), then the FDA (1930)

History of the FDA

Federal Food, Drug, and Cosmetic Act (FD&C Act) 1938 Following the death of the 1906 act Tennessee “wonder sulfa drug” 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

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

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

History of the FDA (cont)

FDA Plan of Action (first) 1985◦ Response to criticism of FDA’s implementation of the 1976

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

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

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

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

What is a Medical Device? Medical Device (section 201 of Federal Food, Drug, &

Cosmetic 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).

Which Class is my Device? Depends mainly on intended use and indications for use

Classification of Medical Devices Class I Medical Devices “General Control”

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

Some class I devices can be exempt from PMN (Pre-Market Notification) and/or GMP (Good Manufacturing Practice)

Examples: manual stethoscopes, surgical scalpels, forceps, wheelchairs, elastic bandages, exam gloves, hand-held surgical instruments

Class II Medical Devices “General and Special Control” Not life sustaining, no risk of life Need additional controls such as performance standards,

post market surveillance, special labeling, patient registries, guidelines, recommendations

Usually exempt from proving safety and efficacy, however FDA may require additional laboratory or clinical studies

Never exempt from PMN or GMP Examples: endoscopes for viewing body cavities, surgical

lasers, powered wheelchairs, infusion pumps, surgical drapes, physiological monitoring

CLASSIFICATION OF MEDICAL DEVICES

CLASSIFICATION OF MEDICAL DEVICES

Class III Medical Devices “General and Premarket Approval”◦ 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

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: indwelling gas analyzers, implanted cardiac pacemakers, balloon

catheters, stents, cardiac arrhythmia alarms, heart valves, breast implants

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, 1976. 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.

Types of Devices In Vitro Diagnostics (IVD)

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.

Types of Devices 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

Types of Devices

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.

Currently being scrutinized by the FDA since a complete DHF and FDA submission is not required.

Doctors must sign waivers saying that they release the company from all liabilities.

FDA Approval Process 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.

FDA Approval Process

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.

Responsibility of the device is now listed

FDA Approval Process

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.

FDA Approval Process

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.

FDA Approval Process

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

FDA Approval Process

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

FDA Approval Process

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.

6o 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.

Quality Departments

FDA Approval Process

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.

FDA Approval Process 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

Example In Industry (Pharmaceuticals)

Example in Industry (Medical Devices)

New Development Product (i.e. at US Endoscopy)

Production Level Device is Ready

In Vitro Testing on Animal Parts

Design Limited Market Release (Clinical Testing on Patients)

Bench Testing (Age, Output Verification, etc.)

Full Market Release

Testing acceptable

Testing acceptable

Testing acceptable

redesign

Formal Application to the FDA

90 or 180 days

FDA Consent Decree What is it?

An agreement between the FDA and a company that outlines steps to return a product to full production

Aligns FDA’s vision of GMP’s with the companies Company has to stop marketing and manufacturing

the product that is not in compliance Unless the device is life saving

FDA Consent Decree What causes it?

Recall of product due to manufacturing defect Failed audit results in “serious” warning letter Series of “less serious” warning letters Failure to comply to inspection reporting in a timely

manner What should a company do?

Reconfigure their compliance procedures to meet FDA requirements