Module 21 2021
©TOPRA ( The Organisation for Professionals in Regulatory Affairs) 2021
Please note that all printed material contained in the course handouts is, unless copyright is assigned elsewhere, the copyright of The Organisation for Professionals in Regulatory Affairs. Such materials are intended for the personal use of the registered students/delegates. Agreement must be reached with the Institute before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form or by any means – that is, electronic, mechanical, photocopying, recording or otherwise.
Module 21 - US Regulation of Medical Devices First Name Last Name
Company
Country
Thiago
Dantas Araujo
Ares Trading SA
Switzerland
Ashleigh
Batchen
MHRA
UK
Joules
Dormer
QED
Ireland
Heidi
Forsyth
Vascutek
UK
Eugenia
Fuhr
Bentley InnoMed
Germany
Barry
Fullard
Invibo
UK
Christina
Hansen
Ralex Consulting
Denmark
Clare
Huntington
Pharmalex
UK
Sukhraj
Kaloya
Vascutek
UK
Ryan
King
Terumo Aortic
UK
Sam
Worrapong Kit-Anan
Guidehouse
UK
Kerrie
Mouncey
Clement Clarke Holdings
UK
Shajel
Panchal Soora
Lightpoint Medical
UK
Rajen
Shallen Patel
MHRA
UK
Julia
Thomson
Vascutek
UK
Ye
Wang
Guidehouse Europe
UK
Elizabeth
Webb
BD Life Sciences
UK
Thomas
Whay
Clement Clarke Holdings
UK
Keri
Wilkie
Vascutek
UK
Annette
Wuestholz
Boehringer Ingelheim
Germany
Module 21: US Regulation of Medical Devices:
LOCATION: TOPRA OFFICE, LONDON, UK / ONLINE
Module Leader(s) : Jonathan Hughes
Date: 3 – 5 March 2021
Day 1: Wednesday 3 rd March 2021
Time
Activity
Speaker
09.00 – 09.30
1. Module Introduction
Jonathan Hughes
2. Introduction to US FDA - History, Structure and Mission of FDA
09.30 – 10.30
Jonathan Hughes
10.30 – 10.45
Refreshment Break
3. Overview of US Regulatory Process and Pathway & FDA Communications / Q-subs
10.45 - 12.15
Jonathan Hughes
12.15 – 13.15
Lunch
4. Classification, Drug Device Listing, Establishment Registration & FDA Database
13.15 – 14.30
Jonathan Hughes
14.30 – 14.45
Refreshment Break
14.45 – 17.00
5. Case Study 1: Classification
Jonathan Hughes
Module 21: US Regulation of Medical Devices:
LOCATION: TOPRA OFFICE, LONDON, UK / ONLINE
Module Leader(s) : Jonathan Hughes
Date: 3 – 5 March 2021
Day 2 : Thursday 4 th March 2021
Time
Activity
Speaker
09.00 – 09.30
6. Recap & Reconnect
Jonathan Hughes
09.30 – 09.40
Short refreshment break
7. Submissions: Pre-Market Notification 510(k)
09.40 – 11.00
Jonathan Hughes
11.00 – 11.15
Refreshment break
8. Submissions: De Novo Reclassification
11.15 – 12.00
Richard Vincins
12.00 – 13.00
Lunch
9. Submissions: PMA Submission
13.00 – 14.30
Richard Vincins
14.30 – 14.45
Refreshment break
10. Submissions: IDE, HDE, and Clinical Investigations
14.45 – 15.30
Richard Vincins
15.30 – 15.45
Refreshment break
15.45 – 17.00
11. Combination Products
Jonathan Hughes
Module 21: US Regulation of Medical Devices:
LOCATION: TOPRA OFFICE, LONDON, UK / ONLINE
Module Leader(s) : Jonathan Hughes
Date: 3 – 5 March 2021
Day 3: Friday 5 th March 2021
Time
Activity
Speaker
09.00 – 09.30
12. Recap & Reconnect
Jonathan Hughes
13. Case Study 2: Submissions
09.30 – 10.45
Jonathan Hughes
Refreshment Break
10.45 – 11.00
11.00 – 11:45
14. Case Study Feedback
Jonathan Hughes
11:45 – 12.45
Lunch
12.45 – 14.30
15. Labelling and Advertising
Richard Vincins
14.30 – 14.45
Refreshment Break
16. Post-Market Requirements: Adverse Event Reporting, Recalls, and Inspections
14.45 – 16.15
Richard Vincins
16.15 – 16.30
Close of Module
Jonathan Hughes
02/03/2021
TOPRA / UoH M.Sc. Medical Device Regulatory Affairs 3 rd - 5 th March 2021
Module 21: Introduction US Regulation of Medical Technology
Jonathan Hughes , Ph.D., FTOPRA JHRA Ltd jhughesra@icloud.com + 44 (0)1494 727101
1
1
Learning Outcomes
On successful completion of the module students will be able to: • Demonstrate a thorough understanding of US medical technology regulation by describing the principles of the regulatory system. • Devise and plan regulatory strategies to enable launch of medical technology on the US market. • Describe the alternate pathways to the US medical technology market and the associated requirements, differentiating between exempt, pre-market notification clearance and pre-market approval products. • Outline the underlying principles and regulatory processes in the US, covering FDA enforcement powers, medical device reporting, quality system regulations, establishment registrations and device listings. • Describe the principle differences between the US and EU medical technology regulatory systems.
2
03/March/2021
M.Sc. US Regulation of Medical Technology – Module 21 Introduction
2
1
02/03/2021
Please …
• Take part • Be vocal • Ask questions • Answer questions • Contribute • Share experience • Work as a team • Have fun
... as much as virtually possible
3
03/March/2021
M.Sc. US Regulation of Medical Technology – Module 21 Introduction
3
M.Sc. US Regulation of Medical Technology – Module 21 Introduction M.Sc. US Regulation of Medical Technology – Module 21 Introduction
4
25/09/2019
03/March/202
4
2
02/03/2021
M.Sc. US Regulation of Medical Technology – Module 21 Introduction M.Sc. US Regulation of Medical Technology – Module 21 Introduction
5
25/09/2019
5
14/02/2017
M.Sc. US Regulation of Medical Technology – Module 21 Introduction M.Sc. US Regulation of Medical Technology – Module 21 Introduction
6
6
3
02/03/2021
Module Team:
• Kay Platt – Education & Apprenticeship Lead (TOPRA) • Laura Brown – Course Director (TOPRA)
• Samantha Cooper – Director of Professional Development (TOPRA) • Jonathan Hughes – Module Advisor / Chair / Speaker (JHRA Ltd) • Richard Vincins – Speaker (The Centre for Global Regulatory Compliance)
25/09/2019
M.Sc. US Regulation of Medical Technology – Module 21 Introduction M.Sc. US Regulation of Medic l Technology – Module 21 I troduction
7
03/March/202
7
Who are the Dream Team?
03/March/2021
M.Sc. US Regulation of Medical Technology – Module 21 Introduction
8
8
4
02/03/2021
Introductions ...
• Name • Affiliation • Medical Device Industry / regulatory affairs experience • US Medical Device regulatory experience • Key objective for this module / What one thing would you like to come away with?
03/March/2021
M.Sc. US Regulation of Medical Technology – Module 21 Introduction
9
Introductions ...
Jonathan Hughes
• Name
JHRA Ltd / Medical Device RA Consultancy
• Affiliation
• MD Industry / regulatory affairs experience 34 years [32 years in medical device regulation] • US Medical Device regulatory experience 28+ years ... started working directly with FDA in 1993; covering all submission types, all classes, including combination products, across multiple therapeutic and technology areas. • Key objective for this module / what one thing would you like to come away with? Ensure you, the delegates, meet your objectives and enjoy a useful and interesting course.
03/March/2021
M.Sc. US Regulation of Medical Technology – Module 21 Introduction
10
5
02/03/2021
US Regulation of Medical Technology
Medical Device?
SOURCE: The Museum of Questionable Medical Devices Online; http://www.museumofquackery.com/welcome.htm 11
11
US v EU Regulation of Medical Technology
25/09/2019
M.Sc. US Regulation of Medical Technology – Module 21 Introduction
12
12
6
02/03/2021
Please …
• Take part • Be vocal • Ask questions • Answer questions • Contribute • Share experience • Work as a team • Have fun
... as much as virtually possible
13
03/March/2021
M.Sc. US Regulation of Medical Technology – Module 21 Introduction
13
Any Questions?
JHRA Ltd. jhughesra@gmail.com +44 1494 727101 Jonathan Hughes, Ph.D., FTOPRA
14
14
7
02/03/2021
M.Sc. Medical Device Regulatory Affairs Module 21: US Regulation of Medical Technologies 3 rd March 2021
Introduction to US FDA History, Structure & Mission
Jonathan Hughes, Ph.D., FTOPRA JHRA Ltd
jhughesra@icloud.com + 44 (0)1494 727101
1
Introduction to FDA - History
Many of key changes and developments in the regulation of drugs and devices have been reactive and driven or hastened by scandals or tragedies promoting action (that may have been previously considered but not acted upon) ...
MSc MTRA: US Regulation - Introduction to FDA
2
2
1
02/03/2021
Introduction to FDA - History
The origins of the FDA can be traced back to the American Civil War (and Mexican American War before) • There were more American deaths (c.620- 850,000) in the Civil War than THE TOTAL in all the wars since: WWI, WWII, Korea, Vietnam, Gulf, Afghanistan, Iraq. • Insanitary conditions, poor understanding of infectious disease transmission, weak/adulterated low quality imported drugs, “quack” remedies and medicine shows, proliferation of patent “medicines” caused or resulted in more than half (400-500,000) of these deaths arising from disease • Many returning seriously wounded soldiers were addicted to Morphine
MSc MTRA: US Regulation - Introduction to FDA
3
3
Introduction to FDA - History
In 1862, president Lincoln appointed Charles M. Wetherill to serve in the new Department of Agriculture (USDA)
1882: Dr Harvey Washington Wiley becomes Chief Chemist in the “ Bureau of Chemistry ” in the USDA – the “Crusading Chemist” began to press for better control of imported medicines (most were imported), proliferation of domestic patent medicines, quack remedy travelling “medicine shows”, as well as food and hygiene
Wiley’s “Poison Squad” – 12 men from the USDA ate a variety of chemical preservatives and colouring agents (e.g.: borax, copper sulphate, formaldehyde, saccharin) in increasing doses to demonstrate deleterious effects
MSc MTRA: US Regulation - Introduction to FDA
4
4
2
02/03/2021
Biologics Control Act of 1902
• Diphtheria Epidemic • 13 children died ... not from diphtheria, but from the anti- toxin used to treat them • Anti-toxin had been contaminated with tetanus during manufacture • Biologics Control Act introduced: • Licensed Facilities • Licensed (Biological) Products • Expiry Dating
MSc MTRA: US Regulation - Introduction to FDA
5
5
Pure Food & Drugs Act of 1906
“The Jungle" by Upton Sinclair caused a public outcry - exposed in graphic detail the practices of the meat packing industry in Chicago
Media coverage of Patent Medicines scandals in popular periodicals
Resulted in 1906 “Pure Food & Drugs Act (“Wiley’s Act”)
MSc MTRA: US Regulation - Introduction to FDA
6
6
3
02/03/2021
Pure Food & Drugs Act of 1906
• Provided for Federal inspection of meat products (creating first Federal inspection programs ) • Forbade manufacture, sale, or transportation of adulterated food products and poisonous medicines • Sherley Amendment of 1912 required that certain specified drugs , including alcohol, cocaine, heroin, morphine and cannabis be accurately labeled with contents and dosage . Previously many drugs had been sold as ”patent medicines” with secret ingredients or misleading labels ( first enforcement mechanism for misbranding )
• Implemented by USDA but paved way for the creation of the FDA
• No premarket safety or effectiveness requirements
Mrs Winslow’s Soothing Syrup for teething, colicky babies, unlabeled yet laced with morphine, killed many infants
MSc MTRA: US Regulation - Introduction to FDA
7
7
Food Drug and Cosmetic Act of 1938
• Elixir sulfanilamide poisoning • More than 100 people died in 1937
• The elixir had been mixed with raspberry flavouring dissolved in diethylene glycol, which was poisonous in combination with the elixir • No animal testing was conducted • Company paid a minimum fine under a technicality of the 1906 Act (Sherley Amendment), which prohibited labeling a drug as an elixir if it did not contain alcohol
FDA formed in 1931 from the “Food, Drug & Insecticide Administration”, which had split from the USDA Bureau of Chemistry in 1927
MSc MTRA: US Regulation - Introduction to FDA
8
8
4
02/03/2021
Food Drug and Cosmetic Act of 1938
The FD&C Act created foundation for FDA regulatory authority • Required pre-market review of the safety of all drugs Sponsors of new drugs submit safety data to FDA before marketing Default review system – 60 days • Required listing of active ingredients with adequate directions for use • Banned false therapeutic claims • Authorized factory inspections and remedy of court injunctions • Introduced “general controls” for (some) therapeutic devices* and cosmetics (there had been no specific reference to medical device regulation prior to FD&C Act of 1938)
* However, only very limited controls and no pre-market review of devices required
MSc MTRA: US Regulation - Introduction to FDA
9
9
And then ...
FDA reviewer Frances Kelsey receives President’s Award for Distinguished Federal Civilian Service
Thalidomide
MSc MTRA: US Regulation - Introduction to FDA
10
10
5
02/03/2021
Thalidomide Tragedy
• “Wonder drug” tranquilizer and painkiller for insomnia, coughs, colds and headaches • Many women took the drug during pregnancy to relieve symptoms of morning sickness • FDA reviewer, Frances Kelsey, had concerns regarding safety of the drug and resisted considerable pressure from industry to approve it • Reports of birth defects were eventually linked to the drug • More than 10,000 children in 46 countries born with serious birth defects
MSc MTRA: US Regulation - Introduction to FDA
11
11
Kefauver-Harris Amendment of 1962
• “Drug Efficacy Amendment” • Required that safety and effectiveness be demonstrated via New Drug Application (NDA) • Introduced concept of Informed Consent in clinical trials • Required that adverse drug reactions be reported to FDA • Required drug advertising to disclose accurate information about side effects and efficacy • Up to 1962 Drug Amendments Act, medical devices were only subject to legal challenge regarding fraudulent devices and proposals for device regulations were included in 1962 draft amendments but were dropped to enable swift passage of the act
MSc MTRA: US Regulation - Introduction to FDA
12
12
6
02/03/2021
Medical Device Regulation?
• Between 1962 and 1976, significant innovation in devices took place and in order to regulate certain devices of concern, FDA declared them “new drugs” and regulated accordingly, these included: • Bone cement • Surgical sutures • Absorbable hemostatic agents/dressings • Intraocular lens • “Soft” (hydrophilic) contact lens • 1968 Radiation Control for Health & Safety Act introduced performance standards for x-rays, etc. • 1969 literature review verifies 10,000 injuries associated with medical devices over 10-year period • Media coverage of pacemaker defects • 1970: The Cooper Committee recommends legislation of medical devices • 1974: The Bureau of Medical Devices and Diagnostic Products is established
MSc MTRA: US Regulation - Introduction to FDA
13
13
Dalkon Shield
Dalkon Shield (IUD) marketed in 1971 • Wicking string caused an increased risk of developing pelvic inflammatory disease • Reports of septic abortion, ectopic pregnancy, and infertility • Device withdrawn from the market in 1973 • Biggest tort liability case since asbestos • Company bankrupted • Safety issues further prompted need for medical device regulation
MSc MTRA: US Regulation - Introduction to FDA
14
14
7
02/03/2021
Medical Device Amendments of 1976
• Ensure the safety and effectiveness of medical devices
• First legislation enabling pre- and post-market controls for medical devices • Provided FDA authority to require testing and premarket clearance and approval of medical devices
• Led to development of Device c-GMP in 1978
• Risk-based classification of medical devices (Class I, II, III)
• Important when considering classification and regulatory pathway today: “Pre-Amendments Devices”
MSc MTRA: US Regulation - Introduction to FDA
15
15
Medical Device Amendments of 1976
Introduced the first meaningful medical device regulatory controls, with provisions and/or requirements for:
• Classification of devices based on level of control necessary and sufficient for safety and effectiveness (risk-based) • Registration of Establishments and Listing of Devices • Premarket Notification [510(k)], when applicable • Premarket Approval (PMA), when applicable [with alternatives for Product Development Protocol (PDP) or Humanitarian Device Exemption (HDE) ] • Conduct of clinical studies under Investigational Device Exemptions (IDE) • Reclassification and exemptions from premarket notification
MSc MTRA: US Regulation - Introduction to FDA
16
16
8
02/03/2021
Medical Device Amendments of 1976
Introduced the first meaningful medical device regulatory controls, with provisions and/or requirements for:
• Definition of medical device (201(h) of the Act) • Led to classification of approximately 1,700 different generic types of devices and grouped them into 19 medical specialties • Required premarket review depending on when the devices were introduced into commercial distribution • “Pre-amendments Device” (Pre 1976): exempted (with conditions) from marketing clearance • “Post-amendments Device” (Post 1976): require marketing clearance
MSc MTRA: US Regulation - Introduction to FDA
17
17
Medical Device Amendments of 1976
Defined medical devices as:
“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 Pharmacopoeia, or any supplement . . . • 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 any of 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 .”
MSc MTRA: US Regulation - Introduction to FDA
18
18
9
02/03/2021
Bjork-Shiley Heart Valve
• Safety concerns relating to Bjork-Shiley Heart Valve (and others)
• Deaths from malfunctions starting in 1982
• Series of recalls and improvements until eventually withdrawn in 1986
• Prompted the Safe Medical Device Act 1990 (and associated Medical Device Amendments 1992 ) ...
MSc MTRA: US Regulation - Introduction to FDA
19
19
Safe Medical Devices Act of 1990
Safety / compliance
• Substantial Equivalence (SE) (re-)defined • Special Controls added • Authorized addition of Design Controls to device cGMPs * • Increased post-market (after-sale) authority • Required Medical Device Reporting for user facilities and distributors for serious injury/death/ malfunction • Post-market surveillance studies and device tracking required for some devices • Added authority to order recalls and assess civil penalties • Repealed need for performance standards for all Class II devices (per Medical Device Amendments of 1976)
* cGMPs later (in 1996) codified as ” Quality Systems Regulations ” under 21CFR820
Amended by 1992 Medical Device Amendments (additional MD Reporting requirements)
MSc MTRA: US Regulation - Introduction to FDA
20
20
10
02/03/2021
FDA Modernization Act (FDAMA)1997
Innovation / access
• Investigational Device Exemptions: • FDA/sponsor meetings on clinical study plans/protocols • Some development and protocol changes w/o notice to FDA • Premarket Approval [PMAs]: • FDA and sponsor meetings to resolve issues during review • Manufacturing changes under Quality System Regulation • Premarket Notifications [510(k)]: • Redefined exemption criteria for Class I devices; and added exemption criteria for Class II devices; • Decoupled quality system compliance and 510(k) clearance • Recognition of Voluntary Standards for PMAs and 510(k)s • De Novo 510(k)
MSc MTRA: US Regulation - Introduction to FDA
21
21
MDUFMA I and II
• Medical Device User Fee and Modernization Act, 2002:
• User fees for premarket reviews linked to performance goals • Establishment inspections may be conducted by accredited third- parties • Paediatric provisions • New regulatory requirements for reprocessed single-use devices • Review of combination products coordinated by a new office (OCP) • Medical Device User Fee and Modernization Act II, 2007: • Renewed and expanded user fee program • Part of the FDA Amendments Act (FDAAA) 2007 which introduced electronic registration and listing and UDI concept
MSc MTRA: US Regulation - Introduction to FDA
22
22
11
02/03/2021
FDA Safety and Innovation Act (FDASIA), 2012: Innovation
• Includes MDUFA III performance goals and user fees renewal • Reauthorizes third-party review • Provides a new de novo pathway for risk-based reclassification of devices • Expands FDA's post-market surveillance capabilities (”Sentinel”) • Shortens timelines for scheduling appeals meeting and issuing decisions • Clarifies “least burdensome” standard
• Introduces implementation of Unique Device Identification (UDI)
MSc MTRA: US Regulation - Introduction to FDA
23
23
21st Century Cures Act 2016
Innovation / expedite product development
• Includes expedited review for breakthrough devices
• Expands ”least burdensome” principles
• Streamlines exemptions from 510(k)s
• Increased population to qualify for HUD designation
• Permits use of central IRB oversight
• Requires FDA to revise regulation on Combination Products
• Process for requests for recognition of a standard
MSc MTRA: US Regulation - Introduction to FDA
24
24
12
02/03/2021
FDA Reauthorization Act (FDARA) 2017
• Reauthorized user fees (MDUFA IV) – user fee for de novo
• Authorized risk-based inspection scheduling
• Decoupled accessory classification from classification of parent
device
• Required FDA to conduct pilot projects for “Real-world evidence” to
improve post-market surveillance
• More devices to be available for third-party review of 510(k)s
MSc MTRA: US Regulation - Introduction to FDA
25
25
US Law and Regulations Timeline
?
Safe Medical Devices Act 1990
21 st Century Cures Act 2016
Drug Amendments 1962
MDUFMA 2002
Food and Drug Act 1906
Medical Device Amendments 1976
QS Regulation 1996
FDASIA 2012
?
MDUFMA II 2007
Drug cGMP’s 1963
Food, Drug & Cosmetic Act 1938
Device cGMP’s 1978
FDAMA 1997
MDUFMA IV 20017
26
13
02/03/2021
History and the FDA today ...
• Understanding FDA is about understanding the history and personalities • https://www.fda.gov/about-fda/fdas-evolving-regulatory-powers/milestones- us-food-and-drug-law-history • “Protecting America’s Health: The FDA, Business and One Hundred Years of Regulation” Philip J. Hilts, Pub: Alfred A. Knopf, Random House, Inc. New York NY, ISBN: 0-375-40466-X
• What is the modern FDA? • FDA evolved from a purely scientific agency to a consumer protection agency with a public health mission
MSc MTRA: US Regulation - Introduction to FDA
27
27
FDA today ...
• What is within FDA’s purview ? • Foods, except for most meat and poultry products, which are regulated by USDA
• Food additives • Infant formulas • Dietary supplements • Human drugs • Vaccines, blood products, and other biologics • Medical devices • Electronic products that emit radiation • Cosmetics • Veterinary feed, drugs, and devices • Tobacco products
• FDA regulates > $1 trillion worth of products each year
MSc MTRA: US Regulation - Introduction to FDA
28
28
14
02/03/2021
FDA today ...
What is NOT within FDAs purview?
Some examples:
• Reimbursement
• Drug pricing
• Health insurance
• Illegal drugs of abuse – e.g.: heroin, marijuana
FDA often shares regulatory responsibilities for certain products with other government agencies (e.g.: CMS)
MSc MTRA: US Regulation - Introduction to FDA
29
29
US Department of Health & Human Services
MSc MTRA: US Regulation - Introduction to FDA
30
30
15
02/03/2021
FDA Facts
• FDA headquarters is based in suburban Maryland
• FDA has 20 district offices across the U.S.
• FDA has over 11,000 employees
• FDA is a Federal Agency
• FDA staff may be Public Health Service Commission Corps
• FDA contracts out some activities
• FDA regulates 25% of U.S. Gross Domestic Product
MSc MTRA: US Regulation - Introduction to FDA
31
31
FDA Organization Overview
Commissioner of Food & Drugs: Janet Woodcock, M.D. (Acting)
14/02/2017
MSc MTRA: US Regulation - Introduction to FDA
32
32
16
02/03/2021
CDRH Organization Overview
MSc MTRA: US Regulation - Introduction to FDA
33
33
CDRH Organization Overview
https://www.fda.gov/about-fda/cdrh-offices/cdrh-management-directory-organization
MSc MTRA: US Regulation - Introduction to FDA
34
34
17
02/03/2021
CDRH Office of Product Evaluation and Quality
https://www.fda.gov/about-fda/cdrh-offices/cdrh-management-directory-organization
35
35
CDRH Office of Product Evaluation and Quality
Previously “Office of Device Evaluation” (ODE), OPEQ n ow has seven (7) Offices of Health Technology (OHTs) = submission reviewing sections : https://www.fda.gov/about-fda/cdrh-offices/office-product-evaluation-and-quality
36
18
02/03/2021
CDRH OPEQ Offices of Health Technologies
https://www.fda.gov/about-fda/cdrh-offices/cdrh-management-directory-organization
37
MSc MTRA: US Regulation - Introduction to FDA
37
CDRH OPEQ Offices of Health Technology 7 (IVDs)
Note: Currently no separate legislation for IVDs v. Medical Devices in US. Subject to change as a result of proposed “VALID Act”
38
38
19
02/03/2021
CDRH OPEQ Office of Regulatory Programs (ORP) [previously Compliance / Inspections / BIMO, etc. Link to FDA Office or Regulatory Affairs (ORA)
Submission support
Imports, exports, registration and listing, inspections, audits and compliance
Market intelligence, recalls, regulatory misconduct, MDR
39
MSc MTRA: US Regulation - Introduction to FDA
39
FDA Office of Regulatory Affairs Organization
14/02/2017
40
MSc MTRA: US Regulation - Introduction to FDA
40
20
02/03/2021
FDA Office of Regulatory Affairs Regional “Field Offices”
https://www.fda.gov/about-fda/contact-ora/ora-district-directors
41
41
FDA Office of Regulatory Affairs Program Areas
https://www.fda.gov/about-fda/contact-ora/ora-field-leadership-contacts
42
MSc MTRA: US Regulation - Introduction to FDA
42
21
02/03/2021
FDA ORA Office of Medical Device & RH Operations
https://www.fda.gov/about-fda/contact-ora/ora-field-leadership-contacts#OMDRHO
43
MSc MTRA: US Regulation - Introduction to FDA
43
FDA ORA: Office of Criminal Investigations
If you are in any doubt as to how serious FDA can be ...
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/criminal-investigations/about-oci
MSc MTRA: US Regulation - Introduction to FDA
44
44
22
02/03/2021
FDA Mission
... Protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices ; and by ensuring the safety of our nation's food supply, cosmetics, and products that emit radiation ... ... advancing the public health by helping to speed innovations that make medical products more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medical products and foods to maintain and improve their health
... ensuring the security of the food supply and by fostering development of medical products to respond to deliberate and naturally emerging public health threats .
MSc MTRA: US Regulation - Introduction to FDA
45
45
CDRH Mission
The mission of the Center for Devices and Radiological Health (CDRH) is to protect and promote the public health • We assure that patients and providers have timely and continued access to safe, effective, and high-quality medical devices and safe radiation-emitting products. • We provide consumers, patients, their caregivers, and providers with understandable and accessible science-based information about the products we oversee. • We facilitate medical device innovation by advancing regulatory science, providing industry with predictable, consistent, transparent, and efficient regulatory pathways, and assuring consumer confidence in devices.
MSc MTRA: US Regulation - Introduction to FDA
46
46
23
02/03/2021
FDA Mission: Summary
• Mission to ... protect, promote and enhance the health of the American people • Safe and wholesome foods • Safe cosmetics • Safe radiological devices • Safe and effective drugs and devices • Concept of public service • Public Health Service Commission Corps • FDA employees strongly believe in their mission • Sometimes siege mentality
MSc MTRA: US Regulation - Introduction to FDA
47
47
FDA History & Mission
The History of Medical Device Regulation is REACTIVE and enforced by PEOPLE WHO BELIEVE IN THEIR MISSION
?
MSc MTRA: US Regulation - Introduction to FDA
48
48
24
02/03/2021
Questions?
Jonathan Hughes, Ph.D., FTOPRA JHRA Ltd jhughesra@icloud.com +44 1494 727101
49
49
Introduction to US FDA History, Structure & Mission
Back-up slides
• 21 st Century Cures Act: • Exemptions • Least burdensome
• Breakthrough Devices program • Software Exclusions • Hierarchy of FDA Requirements
• General Controls • Legal Touchstones
MSc MTRA: US Regulation - Introduction to FDA
50
50
25
02/03/2021
21 st Century Cures Act
• Class I / II Exemptions
51
21 st Century Cures Act
• Least Burdensome
52
26
02/03/2021
53
21 st Century Cures Act
• Breakthrough Devices
54
27
02/03/2021
“Breakthrough Devices”
55
Guidance
56
28
02/03/2021
21 st Century Cures Act
57
58
29
02/03/2021
General Controls
Provisions
• Prohibitions against adulteration and misbranding • Compliance with good manufacturing practices • Labelling • Establishment Registration / Device Listing • Record-keeping
MSc MTRA: US Regulation - Introduction to FDA
59
59
Legal Touchstones
• Licensed products • Licensed facilities • Adulteration: contaminated, filthy, putrid, wrong strength / potency, unapproved • Misbranding: false, misleading, mis-labeled, mis-claimed, wrong quantity, not cleared for commercial distribution
MSc MTRA: US Regulation - Introduction to FDA
60
60
30
02/03/2021
M.Sc. Medical Device Regulatory Affairs
Module 21: US Regulation of Medical Technologies 3 rd March 2021
Overview of US Regulatory Process & Pathways
Jonathan Hughes, Ph.D., FTOPRA JHRA Ltd jhughesra@icloud.com + 44 (0)1494 727101
1
Regulatory Agency:
• FDA provides federal oversight of food, drugs, devices , biologics, combination products and other health related products in the US
• Established originally in 1862 as the Bureau of Chemistry in the US Department of Agriculture, renamed FDA in 1931, and first introduced the Food & Drugs Act in 1906, the Food, Drug & Cosmetic Act (FD&CA) in 1938 and the Medical Device Amendments Act in 1976 • The FDA includes the following centers and offices relevant to medical devices and related products: • Center for Devices & Radiological Health (CDRH)
• Center for Biologics Evaluation & Research (CBER) • Center for Drug Evaluation & Research (CDER) • Office of Combination Products (OCP)
2
1
02/03/2021
Legislative Framework
Food Drug & Cosmetic Act
SEC. 201. [21 U.S.C. 321] covers food, cosmetics,
drugs and devices (among other product) regulations:
• Medical Device regulations codified in 21 CFR 800-898 (900, 1000-1050)
• Drug regulations codified in 21 CFR 200-369
• Biologic regulated under Public Health Service Act (42 U.S.C. 267), codified in 21 CFR 600-680
• Combination Product regulations codified in 21 CFR 3 - 4:
• 1976 Medical Device Amendments • 1978 GMPs come into force for medical devices • 1990 Safe Medical Devices Act - substantial equivalence defined, recall requirements strengthened, product jurisdiction • 1996 cGMP requirements revised to form Quality Systems Regulations (QSRs 21 CFR 820) • 1997 FDA Modernization Act (FDAMA) - Class I and II exemptions, pre-IDE meetings, QS compliance changes • 2002 Medical Device User Fee & Modernization Act (MDUFMA) - device user fees, third-party inspection, OCP • 2007 FDA Amendments Act (FDAAA) - renewed and expanded user fees program (MDUFA II) • 2012 FDA Safety & Innovation Act (FDASIA) - clarifies “least burdensome” standard, device modifications requiring approval, modified de novo process and sets out UDI regulation and Sentinel post-market surveillance program • 2016 21 st Century Cures Act – revision of policies and clarified digital health product regulation • 2017 FDA Reauthorization Act (FDARA) – reauthorized user fees (MDUFA IV) and various other new provisions
3
Regulatory Framework
US Food, Drug and Cosmetic Act Codified by 21 CFR 800
800 801 803 806 807 808 809 810 812 813 814 820 821 822 830 860 861 862 864 866 868 870 872 874 876 878 880 882 884 886 888 890 892 895 898
General Labeling
801 Labeling 803 Malfunction Reporting 806 Recalls 807 Facility / Device Listing 809 In-Vitro Diagnostics 812 Investigational Exemption 814 Premarket approval 820 Quality system regulation 830 Unique Device Identifier
Medical device reporting
Medical devices; reports of corrections and removals
Establishment registration and device listing for manufacturers and initial importers of devices Exemptions from federal preemption of state and local medical device requirements
In vitro diagnostic products for human use
Medical device recall authority Investigational device exemptions
[reserved]
Premarket approval of medical devices
Quality system regulation
Medical device tracking requirements
Postmarket surveillance Unique device identification
Medical device classification procedures
Procedures for performance standards development Clinical chemistry and clinical toxicology devices
860
Hematology and pathology devices Immunology and microbiology devices
Anesthesiology devices Cardiovascular devices
Dental devices
Ear, nose, and throat devices Gastroenterology-urology devices General and plastic surgery devices General hospital and personal use devices
Device Classifications
Neurological devices
Obstetrical and gynecological devices
Ophthalmic devices Orthopedic devices
Physical medicine devices
Radiology devices Banned devices
892
Performance standard for electrode lead wires and patient cables
4
2
02/03/2021
Fundamentals of US Law and Regulation
• Laws - system of rules, enforced through a set of regulations • Regulations – legal restrictions promulgated by government authority, i.e., Food and Drug Administration (FDA) • Code of Federal Regulation (CFR) Part 21 • Guidance – represents FDA policy, industry and the public • Processing, content, and evaluation of regulatory submissions • Design, production, manufacturing, and testing of regulated products • Inspection and enforcement procedures • Practice – day-to-day interpretation of FDA policy and guidance
5
Pathway to Market - Overview
START:
Product Designation Medical Device?
Establishment Registration Device Listing Post-market activities
Classification
In conjunction and in parallel with device design and development plan
Submission Route
FDA Clearance or Approval
Implement Quality Systems
Submit to FDA CDRH (or CBER)
Development & Testing
6
3
02/03/2021
Medical Device? (Definition)
Section 21 (h) of the Food, Drug & Cosmetics Act [21 U.S.C. §321 (h)] provides the following definition for a medical device in the US: “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 Pharmacopoeia, 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.”
7
Medical Device?
Phrenology device
Breast pump
Dr Kellogg’s
Dr Bell Electro Appliance
Heidelberg Belt
Vibratory Chair
• SOURCE: The Museum of QuestionableMedical Devices Online; http://www.museumofquackery.com/welcome.htm
8
4
02/03/2021
Product Designation (Medical Device?)
Medical Intended Use ... diagnosis, treatment, prevention of disease and/or intent to affect / modify bodily function
Primary mode of action achieved
Derived or reliant on biological material
by chemical action or or being metabolised?
YES
NO
Drug (CDER) [or Biologic (CBER)]
Request for Designation (RFD)
Center Jurisdiction
Device (CDRH) (or CBER)
?
D
Office of Combination Products
9
Classification
Risk-based classification based on historical precedence and defined product groupings and types (defined by medical / surgical specialty, listed in 21 CFR 862-892)
• Class I (lower risk / “general controls”)
• Class II (moderate risk / “general and special controls”)
• Class III (higher risk / “general controls” and pre-market approval)
• Unclassified
Level of Regulatory Control – sufficient to provide ”reasonable assurance of safety and effectiveness”
High
High
Product Risk Class
Medium
Medium
Low
Low
10
5
02/03/2021
Submission Route
Q
• “ Exempt ”
E
(no submission)
• “Premarket Notification” or “ 510(k) ” (submission for pre-market clearance)
K
• “ De novo ”
DEN
(petition for reclassification)
• Premarket Approval (PMA) (pre-market submission for approval)
PMA
• Humanitarian Device Exemption (HDE) (submission for orphan use)
HDE
11
Submission Route
E
Exempt Devices:
• Exempt from Premarket Notification or Approval ( no pre-market submission to FDA required )
• Most Exempt Devices fall in Class I but some are Class II devices
• Establishment Registration and Device Listing is required
• Quality Systems Regulations:
• Class I devices may also be exempt from some elements of the Quality Systems Regulations, such as Design Controls
• General Controls and Complaint Files , however, apply to all devices
• General Controls and Complaint Files include labelling and medical device reporting (MDR) requirements
12
6
02/03/2021
Submission Route
Premarket Notification “510(k)”
K
• Determination of Substantial Equivalence (SE) • Based on intended use and technological characteristics of “Predicate” 510(k) device(s) (or “Pre-amendment” device in commercial distribution before 1976) 510(k) filing : • Key content: substantial equivalence discussion, indications for use, summary of technical characteristics (clinical data not mandatory) • Fee ~ $12.4K ($3.1K SBD) • 90 day review cycle (clearance usually within 3-9 months) • Constitutes FDA “ clearance ” not approval for placing device into interstate commerce •
• Most 510(k) devices fall in Class II but some are Class I, Class III or Unclassified devices
• Quality Systems Regulations apply, including design controls
• Establishment Registration and Medical Device Listing is required
13
Submission Route
“ De Novo”
DEN
• Evaluation of automatic Class III designation - “ de novo ” is a reclassification petition procedure • Applies to low-medium risk devices where no “predicate” exists • Device is not subject to premarket approval • Filed directly with FDA (previously could only apply or “petition for reclassification of automatic class III” after FDA provided a “Not Substantially Equivalent” determination via the 510(k) process) • Fee: $109.7K ($27.4K SBD ) • 150 day review cycle (clearance usually within 6-9 months; recent variance 6- 15m, *historically slow process of up to 36m+) • Special Controls apply for “de novo” devices, developed during the submission / classification process • Quality Systems Regulations apply, including design controls • Establishment Registrations and Medical Device Listing is required
* Fees introduced FY 2017 to speed up review
14
7
02/03/2021
Submission Route
Pre-Market Approval PMA
• PMA devices are Class III / high risk devices
•
PMA filing : • Key content: all relevant technical, non-clinical and clinical data (mandatory) • Fee ~ $365.7K ($91.4K SBD) • 180 day review cycle (approval usually within 6-18 months; mean 262 FDA days)
• Quality Systems Regulation apply - facility pre-market inspection
• Establishment Registrations and Medical Device Listing is required
• Constitutes FDA approval for placing device into interstate commerce
• Provides PMA approval holder with stronger strategic market exclusivity position (no cross referencing or predication of PMA devices)
15
Submission Route
Humanitarian Device Exemption
HDE
• HDE applies to “ Humanitarian Use Devices ” (HUD’s) intended for <8,000 patients in US / year
• Two stage process: (1) obtain HUD status from FDA Office of Orphan Product Development (statutory 45 day timeframe); (2) obtain HDE from CDRH
•
HDE filing : • Same as PMA, except: exempt from user fee and from effectiveness requirements (i.e.: clinical evidence limited to show probable benefit outweighs risk ) • 105 day review cycle (assuming no additional data requirements or amendments)
• Must label as “HUD” and limited effectiveness data
• Requires IRB approval for use in facilities and profit restrictions apply based on research and development and fabrication / distribution costs
16
8
02/03/2021
[Proposed New] Submission Route
FDA’s Digital Health Software Pre-Certification Program
• Additional / New “Submission” Route / Program for digital health software • Pilot program – currently in process with nine (9) pilot companies • Built around FDA’s “Total Product Lifecycle (TPLC) Approach”, based around:
• Excellence Appraisal • Review Determination • Streamlined Review • Real-World Performance
17
[Proposed New] Submission Route
18
9
02/03/2021
[Proposed New] Submission Route
FDA’s Digital Health Software Pre-Certification Program
19
[Proposed New] Pre-Cert Program
20
10
02/03/2021
[Proposed New] Pre-Cert Program
14 September 2020
21
Pre-Cert Program: further developments for AI / ML
January 2021
22
11
02/03/2021
Implement Quality Systems
Quality System Regulations (“QSRs”) [21 CFR 820]
• Apply to all devices (excluding specific elements for some “Exempt Devices”) • Includes requirements for: • Management Responsibility • Design Controls • Document Controls • Purchasing Controls • Identification and Traceability • Acceptance Activities • Non-Conforming Product • Corrective and Preventive Action (CAPA) • Labeling and Packaging Controls • Handling, Storage, Distribution and Installation • Records (including Complaint Handling) • Servicing • Statistical Techniques • QSRs apply post-market but also need to be in place for clinical supplies and
product development (use of design controls and human factors) • FDA inspections (periodic or for cause) conducted against QSRs
23
Development & Testing
Key stages of medical device development and testing per FDA CDRH Innovation White Paper:
The image part with relationship ID rId3 was not found in the file.
Risk Management throughout
Key data requirements for device development / submissions: • Laboratory / bench testing • Biocompatibility testing • Sterilization validation • Shelf-life and device lifetime testing • Software validation • Clinical testing Illustrative list - non-exhaustive and not all necessarily required
Design Controls apply in the shaded design + development and investigational phases
24
12
02/03/2021
Development & Testing
Q
Clinical Investigations
• Required for PMA applications and some 510(k), de novo and HDE filings
• Conducted under “Investigational Device Exemption” (IDE) • Abbreviated requirements for “Non-Significant Risk Devices” (IRB plus labelling) • Full IDE for “Significant Risk Devices” requires IDE filing and approval by FDA • IRB(s) may decide “Significant Risk” status (FDA decision binding if IRB undecided or conflicting) • IDE Filing : • Key content: all relevant technical, non-clinical and clinical data, protocol • 30 day review cycle • No fee • List on www.clinicaltrials.gov • Foreign clinical studies / data may be accepted by FDA if the study data, subject population and medical practice is relevant to the US
25
Submit to FDA CDRH (or CBER)
FDA Clearance or Approval
Submission format, content and review timeframe vary by type of submission:
• 510(k) application and clearance: • 90 day review cycle, assumes no questions or deficiencies identified during review (3-9m) • Format and content defined in guidance - usually single volume, relatively straightforward • $12K fee • PMA application and approval: • 180 day review cycle, assumes no questions or deficiencies identified during review (6-18m) • Modular PMA option allows for earlier / ongoing submission through development plan • Format and content defined in guidance - multiple volumes, substantive submission • $366K fee • De novo reclassification order and decision: • 150 day review cycle, assumes no questions or deficiencies identified during review (6-15m) • Format and content more variable, dependent on interaction between FDA and sponsor • $110K fee • HDE (and HUD) application and approval: • 30 day initial review, with 75 day substantive review cycle • Format and content as for PMA, though exemption or limitation for clinical effectiveness data • Submit all applications to CDRH, except for devices involved in the collection, processing, testing, manufacture and administration of licensed blood, blood components and cellular products, which should be submitted to CBER. CBER also regulates all HIV test kits.
26
13
Made with FlippingBook Learn more on our blog