1. Device regulations USA Dr Phil Warner

2. USA Regulations MEDICAL DEVICES Food, Drug & Cosmetics Act Medical Device Amendments of 1976 (and other things) Food & Drug Administration – FDA Class I, II, III devices General controls Notification: 510(k) Pre-Market Approval: PMA

3. USA Regulations FDA have wide ranging powers beyond medical devices and medicines Power to enter & inspect manufacturers Law Enforcement department of the US Government In extreme circumstances, within the US, they turn up in uniform with badges and guns ( Or they bring the US Marshals or National Guard)

4. USA Regulations GENERAL CONTROLS Prohibition of ‘adulteration’ and ‘misbranding’ Records and reports Establishment registration and device listing Labelling Design and produce according to GMP Medical Device Reports (MDRs)

5. What Applies FDA 21 CFR 820 applies to Medical devices It is a quality system US Law applies to quality systems FDA inspections and consequences are more serious than notified body inspections

6. FDA 21 CFR 820 Includes Design control Document control Purchasing control Identification and traceability Production and process control Acceptance control Non-conforming product

7. FDA 21 CFR 820 Labelling and packaging Handling and storage Distribution and Installation Records Servicing Statistical Techniques Corrective and Preventative Actions

8. Pre-Market Assessment FDA requires a Pre-Market Assessment (PMA) It is either: - Substantial equivalence to a predicate device (510K) - Scientific and regulatory review to evaluate safety and effectiveness of class III devices – “sufficient valid scientific evidence

9. USA Regulations 510K New Class II devices and some Class I / III devices And some design changes to existing devices Notification procedure 90-day period Must wait for marketing clearance letter Special, Abbreviated, and Traditional formats Demonstrate ‘substantial equivalence’ ‘Predicate device’ Same intended use & technological characteristics

10. USA Regulations PRE-MARKET APPROVAL Most new Class III devices And design changes PMA Supplement or new PMA Approval process Very thorough (tortuous) review Valid scientific data Demonstrate reasonable safety & effectiveness No third-party review All reviews by FDA staff ‘Panel’ review in some cases

11. EU Regulations Medical Device Directive LOW MEDIUM HIGH Class I Class IIa Class III Premarket Approval - EC Design Certificate Listing Self-certification - Declaration of Conformity Class IIb

12. USA Federal Regulations LOW MEDIUM HIGH Class I Class II Class III Premarket Approval - PMA Evidence of safety and effectiveness Listing or Premarket Notification - 510k Evidence of substantial equivalence +/- clinical data

13. US vs. EC Substantial Equivalence In US all new devices or devices used for a new intended use are automatically Class III Manufacturer can petition FDA to reclassify device to Class II as “substantially equivalent” by filing a 510k submission Clinical data may be needed to get 510k approval

14. EU Regulations Medical Device Directive –And national ‘transpositions’ 25 national ‘Competent Authorities’ –More than 40 notified bodies Class I, IIa, IIb, III Multiple ‘conformity assessment’ routes –Assessment by Notified Bodies –Certification and self-declaration –CE-Mark

15. Enforcement consequences EU Notified Body usually issues minor and major non-conformities Removal of certification for serious major non- conformity or failure to implement adequate CAPA –Without valid certificate – no product can be placed on the market And/or enforced Field S afety Corrective Action

16. Enforcement consequences EU If Notified Body does not get resolution –Escalates to Competent Authority MHRA can prosecute –Max 2 years jail + unlimited fine

17. Enforcement consequences USA Auditors issue Form 483 – recorded observations during an establishment inspection –Voluntary action indicated –Official action indicated Warning Letter follows if insufficient or unacceptable action taken Regulatory action if follow up from company still not sufficient

18. Enforcement consequences USA Regulatory actions –Warning letter –Civil penalty –Administrative detention (30 days detention of devices allowed whilst deciding!) –Recalls by FDA –Import alerts –Automatic detention

19. Enforcement consequences USA Administrative actions include –Seizure of product –Injunctions –Prosecutions under judicial system Felony  up to 5 years jail + $10,000 fine Misdemeanour  up to 1 year jail + $5,000 fine Not following GMPs comes under a charge of adulteration

20. Enforcement consequences USA Everything from a Form 483 on can be immediately in the public domain

21. Case Study Mobile Bearing Knee Total knee replacement (TKR) with a rotating platform bearing on the tibial component An alternative to TKR with a fixed bearing EC –Class III (after recent upclassification) –Literature route used for CE Marking US –FDA declined reclassification petition –Class III, needs an IDE and PMA

22. US vs. EC Approvals All EC regulated Clinical Investigations need prior approval/notification from Competent Authority and Ethics Committee All US Investigational Device Exemption (IDE) clinical studies need prior approval from FDA (if significant risk) and Institutional Review Board (IRB)

23. US vs. EC Postmarketing Clinical Studies EC MEDEV 2.2.12 (2004) Guidelines on Post Market Clinical Follow-up General requirements for PMS clinical follow-up studies – manufacturer decides, Notified Body audits US Formal PMS clinical studies may be mandated by FDA for Class III devices approved under PMA No requirements for 510k approved devices

24. USA vs EU Regulations Supranational Copied by other countries Third of World Market Competent Authorities Notified Bodies ISO 13485 Options for compliance Government agencies involved directly and not always actively Local Representative required Regulators not ‘feared’ National Less copied Third of World Market FDA No role for Notified Bodies 21 CFR 820 (QSR) Proscriptive Government agency involve directly and actively Local Representative required Regulators ‘feared’