Michael Jordan and Jeff Beegle October 23 nd , 2013

1. Food and Drug Administration Michael Jordan and Jeff Beegle October 23nd, 2013

2. 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

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 • 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.

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. The History of the FDA

8. 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)

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

17. 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).

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

19. 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

20. Classification of Medical Devices • 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

21. 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

22. 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.

23. 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.

24. 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

25. 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.

26. 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.

27. 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

28. 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.

29. 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.

30. 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

31. 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

32. 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

33. 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.

34. 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

35. Example In Industry (Pharmaceuticals)

36. Example in Industry (Medical Devices) New Development Product (i.e. at US Endoscopy) Production Level Device is Ready In Vitro Testing on Animal Parts redesign Testing acceptable Bench Testing (Age, Output Verification, etc.) Testing acceptable Design Limited Market Release (Clinical Testing on Patients) Formal Application to the FDA Testing acceptable Full Market Release 90 or 180 days

37. 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

38. 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