Kevin Daly-Lunch & Learn Presentation October 28, 2016

FDA Regulations and Medical Device Pathways

to Market

Kevin Daly Consulting, LLC

October 28, 2016

2Kevin Daly Consulting, LLCOctober 28, 2016

Determining Regulatory Requirements

• Definition of a Medical Device– An instrument, apparatus, implement, machine, contrivance,

implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:• Recognized in the official National Formulary, or the United

States Pharmacopia, or any supplement to them,• intended for use in the diagnosis of disease or other

conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or

• intended to affect the structure or 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 or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.



• Step 1 - Define “Intended Use” and “Indications for Use”– Example: A scalpel’s Intended Use is to cut tissue, and may have

Indications for Use for “for making incisions in the cornea”

• Step 2 - Find FDA Regulation Number and Product Code – Find matching description of the device and its Intended Use in

Title 21 of the Code of Federal regulations (CFR) Parts 862-892, or FDA “Product Code” database• FDA has classified and assigned regulation numbers to over

1,700 distinct types of devices within 16 medical specialties



– Description will include:• Device class (i.e. Class I, II, or III), and

– Information about premarket requirements (i.e. 510(k) exempt, 510(k) required, PMA required)

– GMP requirements of QSR (Quality System Regulation) - exempt or non-exempt

862 = Chemistry/Toxicology 864 = Hematology/Pathology 866 = Immunology/Microbiology 868 = Anesthesiology 870 = Cardiovascular 872 = Dental 874 = Ear, Nose and Throat 876 = Gastro/Urology

878 = General Plastic Surgery 880 = General Hospital 882 = Neurological 884 = Obstetrical/Gynecological 886 = Ophthalmic 888 = Orthopedic 890 = Physical Medicine 892 = Radiology

21 CFR Sections within 16 Medical Specialties



• Step 3 - Find information on previously cleared/approved devices– FDA maintains databases listing all previously cleared/approved

devices– 510(k) Summary or PMA Summary of Safety and Effectiveness

provide helpful information as to the required data submission requirements for new devices

• If no appropriate match can be found– Submit 513(g) Request for Information to the FDA

• FDA will respond within 60 days as to the risk classification and other requirements of the FD&C act

• FDA responses DO NOT constitute FDA clearance or approval for distribution


FDA Medical Device Regulatory Requirements• Class I device requirements

– Typically exempt from Premarket Notification (510(k)) submission requirements

– Subject to “General Controls” (i.e. provisions that relate to adulteration, misbranding, facility registration and device listing, records and reports, recall reporting, adverse event reporting, custom devices, and good manufacturing practices)

– Exempt from compliance with design controls (21 CFR 820.30), except for devices with “automated with computer software”

– May or may not be exempt from GMP requirements of QSR• All Class I sterile medical devices are not exempt from the

GMP requirements of the QSR (all provisions except design controls)


FDA Medical Device Regulatory Requirements• Class II device requirements

– Most require Premarket Notification (510(k)), but some are exempt

– Full compliance with QSR (including design controls)• Register manufacturing facility and list devices within 30 days

after 510(k) clearance

• Class III device requirements– Most require Premarket Approval (PMA)– Full compliance with QSR (including design controls)

• FDA facility pre-inspection required before distributing first device


510(k) Submissions• What “510(k)” means

– Refers to Section 510(k) of the Food, Drug, and Cosmetic Act– Regulations defined in 21 CFR §807 Subpart E– Must demonstrate that new device is “substantially equivalent” to a

predicate (legally marketed in U.S.) device • 3 types: Traditional, Abbreviated, Special

– Traditional – for any “original” 510(k), or modification to a previously cleared device• FDA clearance typically in ~4-6 months

– Abbreviated – use data summaries showing compliance with FDA recognized consensus standards and guidance documents• FDA clearance typically in ~4-6 months

– Special – for a modification to a device that has been previously 510(k) cleared• Uses summary information from design control process as basis

for clearance• Faster clearance times (~30 days)


510(k) Submissions

• What is Substantial Equivalence (SE)?– Demonstration that a new device, as compared to a predicate

device, has… • The same intended use and • The same technological characteristics, or

– that differences in technological characteristics do not raise different questions regarding safety and effectiveness.

• What is a Predicate Device?– A legally marketed device, previously cleared through the 510(k)

process (mainly), that is used for comparison to a new device for the purpose of determining substantial equivalence (21 CFR 807.92(a)(3)).

• When is a 510(k) Typically Required?– Introducing a device to the market for the first time – Changing the indications for use of a previously cleared device – Making significant modification(s) to a previously cleared device


1. Medical Device User Fee Cover Sheet (Form FDA 3601)

2. CDRH Premarket Review Submission Cover Sheet

3. 510(k) Cover Letter 4. Indications for Use Statement 5. 510(k) Summary or 510(k)

Statement 6. Truthful and Accuracy

Statement 7. Class III Summary and

Certification8. Financial Certification or

Disclosure Statement 9. Declarations of Conformity and

Guidance Documents 10.Executive Summary

11.Device Description 12.Substantial Equivalence

Discussion 13.Proposed Labeling 14.Sterilization and Shelf Life 15.Biocompatibility 16.Software description17.Electromagnetic

Compatibility and Electrical Safety

18.Performance Testing – Bench19.Performance Testing - Animal 20.Performance Testing -

Clinical

510(k) Submissions

20 Elements (not trivial):


510(k) Submissions

• 510(k) Test Data• Typically requires side-by-side testing to predicate device unless

an FDA recognized consensus standard or device-specific FDA guidance document exists

• Need statistically valid sample size• 510(k)s typically 100-200 pages long• Includes completion of 24-page FDA “Acceptance Checklist”

• FDA will refuse to accept if information missing• Reusable devices

• Manufacturer must validate cleaning, disinfection, and sterilization procedures

• Duodenoscope infections and deaths have heightened FDA validation requirements


510(k) Submissions

• Upon FDA receipt– By day 7 – FDA acknowledgement letter– By day 15 – FDA conducts “Acceptance Review”– By day 60 – FDA conducts “Substantive Review”

• Requests for minor additional information frequently by email• Requests for major additional information – FDA sends

deficiency letter, and 510(k) review is placed on hold– By day 90 – FDA sends final decision, or– By day 100 – FDA provides “Decision Communication” identifying

outstanding issues.


Other FDA Market Clearance Pathways

• De Novo Submission (21 CFR §513(a)(1)) of FD&C Act– Entirely new devices automatically considered Class III– Includes devices of low risk– File de novo submission for marketing approval as Class I or II

device– Must contain all known information on safety and efficacy of the

device– When approved, may serve as a “predicate” device for future

510(k) submissions.– Average time to complete FDA review is ~1 year– No FDA user fee


Other FDA Market Clearance Pathways

• Humanitarian Device Exemption (“Orphan Device”)– Applies if intended to treat a disease in <4,000 patients annually– No comparable device currently available– Similar to PMA (clinical trials needed)– Must demonstrate safety and “probable benefit” (as opposed to

safety and “efficacy”)– Long approval times (~1-1.5 years)

• Premarket Approval (PMA) Application– Required for highest risk (Class III) devices– Large clinical studies normally required– Must demonstrate device safety and “effectiveness”– FDA “approves” or “disapproves” the PMA– Long approval times (~1-1.5 years)


FDA Pre-Submissions

• FDA Q-Sub (Request for Pre-Submission meeting)– Relatively new opportunity to obtain FDA input on adequacy of

bench, animal, and clinical test protocols– Highly valuable for obtaining confirmation of adequacy of

planned bench, animal, and/or clinical trials– No user fee– FDA meeting, teleconference, or written reply within ~90 days– FDA response does not provide marketing clearance; for

information only


Quality System Requirements• Class I devices – if exempt from GMPS

– Subject to compliance with FDA “General Controls”, “General Controls” • Adulteration• Misbranding• Facility registration and device listing• Recalls• Unique device identifier (UDI)

• Class I devices – if not exempt from GMPS– Comply with “General Controls” and all GMP elements of Quality

System Regulation (21 CFR §820), except (unless specified) Design Controls (21 CFR §820).


21 CFR §820 – Early Development Requirements• 820.30 Design Controls

– Applicable to all class II and III and the following class I devices – Describe design and development activities– Design input

• Note: Standard practice is to initiate a Risk Analysis early in the design and development process in accordance with ISO 14971

– Design output– Design review– Design verification– Design validation


21 CFR §820 – Quality System Regulation

Why Design Controls?

How the CustomerExplained itHow the ProjectManagerUnderstood ItHow R&DDesigned ItWhat the CustomerReally Needed


IDE (Investigational Device Exemptions)

• 21 CFR §812 Investigational Device Exemptions (IDEs)– Requirement for conducting clinical trials– 2 Types of IDEs

• Significant Risk (SR) IDE – Requires FDA pre-approval (30 days)• Non-Significant Risk (NSR) IDEs – Requires only Institutional

Review Board (IRB) approval– IDE Sponsor (e.g. Company) determines risk– If IRB disagrees and believes is significant risk study,

Sponsor must report to the FDA


FDA Regulation of Medical Device Apps (MMAs)• Mobile Application is a “Medical Device” if it:

– Is used as an accessory to an already-approved medical device– Transforms a mobile device such as a smartphone or tablet into

an actual medical device providing diagnostic or therapeutic assistance

• Will my medical mobile app be regulated as a medical device?– Key FDA Guidance at:

http://www.fda.gov/downloads/MedicalDevices/.../UCM263366.pdf – States: When the intended use of a mobile app is for the

diagnosis of disease or other conditions, or the cure, mitigation, treatment, or prevention of disease, or is intended to affect the structure or any function of the body of man, the mobile app is a device.

http://www.fda.gov/downloads/MedicalDevices/.../UCM263366.pdf

http://www.fda.gov/downloads/MedicalDevices/.../UCM263366.pdf


FDA Regulation of Medical Device Apps (MMAs)• Examples of MMAs Regulated by the FDA

– Sensor connected to mobile platform to measure and display electrocardiograph (ECG)

– Use accelerometer to measure degree of tremor caused by certain diseases.

– Use sensor to monitor physiological parameter (e.g. limb movement, electrical activity during sleep) for use in diagnosing disease or conditions such as sleep apnea.

– App as attachment to mobile platform to measure blood glucose levels


FDA Regulation of Medical Device Apps (MMAs)• Examples of MMAs NOT Regulated by the FDA

– Medical dictionaries or encyclopedias of first-aid or emergency care information

– Apps used for medical training (e.g. anatomy diagrams, games that simulate cardiac arrest scenarios for health professional training

– Help manage shifts for doctors or manage schedules– Tools, quizzes, games, questionnaires to help patient general

health and wellness (e.g. calorie consumption, benefits of physical activity)

– Provide information about gluten-free food products or restaurants


FDA Regulation of Medical Device Apps (MMAs)• Examples of MMAs With FDA “Enforcement

Discretion”– MMAs meet regulatory definition of “device” but pose minimal

risk– From FDA Guidance Document and http://

www.fda.gov/MedicalDevices/DigitalHealth/MobileMedicalApplications/ucm368744.htm • Track a normal baby’s sleeping and feeding habits• Educational reminders or motivators to smokers trying to quit• Track asthmatics inhaler usage• Allow patient to collect, track, and share trend data such as

blood pressure, blood glucose with health care provider or upload to online database

• Allow patient or caregiver to call pre-specified emergency call center

• Lists of signs and symptoms on when to consult a health care provider

http://www.fda.gov/MedicalDevices/DigitalHealth/MobileMedicalApplications/ucm368744.htm





FDA Regulation of Medical Device Apps (MMAs)• What to do when unsure…

– There is no definitive list– Check FDA website for new guidance documents (key words:

“mobile medical applications”)– 513(g) request for classification information ($1,583 for small

business)

• Other Issues to consider– FDA guidance documents on software design and validation– FDA guidance on cybersecurity– FDA guidance on human factors and usability– AAMI ANSI IEC 62304:2006 - Medical Device Software - Software

Life Cycle Processes– IEC 60601-1 requirements for Programmable Electrical Medical

Systems– Other (biocompatibility, sterilization, packaging, labeling, etc.)


FDA Medical Device Regulatory Requirements

Thank you!

Questions?

Email: [email protected]

Kevin Daly-Lunch & Learn Presentation October 28, 2016

Education

Transcript of Kevin Daly-Lunch & Learn Presentation October 28, 2016