US regulations. Tom Ståhlberg FiHTA

Transcription

1 US regulations Tom Ståhlberg FiHTA

2 Where do you want to be? Do you?

3 US FDA US FDA and the rest of the world US FDA in general (Design control in general) (Design control elements)

4 Regulation through: 1. Product registration Products categorized according to their risk USA, Canada, Japan, China: Classes EU (IVD): Annex II list A and list B, Self-Testing and General Low risk products High risk product less direct supervision by authorities should be the focus of authorities!

5 Regulation through: 2. Quality Management System Product development Corrective and Preventive Actions Production Management Materials Equipment and Facility Documentation QSR and ISO 13485:2003

6 Regulated industry Consumer protection In control Shall be written Shall be followed

7 Quality System Regulations, QSR Other related regulations! Guidance documents and their drafts Other unrelated regulations Federal vs. State laws Recognized standards, e.g. CLSI

8 QMS standards ISO 9001:2003 General quality management system standard not enough for medical device manufacturers Still needed: recognized by customers and US FDA ISO 13485:2003 Medical devices Quality management systems Requirements for regulatory purposes Recognized consensus standard by US FDA (although still asking only for ISO 9001:2003 in Factory Profile); equivalent to QSR

9 Also ISO e.g. among the recognized standards ISO/TC 212 Clinical Laboratory testing and IVD Test Systems CLSI secreteriat ISO/TC 210 Quality Management and Corresponding General Aspects for Medical Devices CEN/TC 140 In Vitro Diagnostic Medical Devices OBS! EU specific!

10 CLSI background 1969 National Committee for Clinical Laboratory Standards (NCCLS) 1970 Clinical and Laboratory Standards Institute (CLSI) To be the leader in clinical and laboratory standards to improve the quality of medical care To promote best practices in clinical and laboratory testing throughout the world, using a consensus-driven process that balances the viewpoints of industry, government, and the healthcare professions

11 US FDA US FDA and the rest of the world US FDA in general (Design control in general) (Design control elements)

12 US FDA in general Structure of US FDA Importing to USA Recognized standards QSR Inspections Enforcement Some special questions

13 Importing into USA USA laws does not apply in Finland, but if you want to import into USA: All foreign-produced products subject to review by FDA when offered for importation FDA has authority to: Sample/examine products Permit entry of products Detain/refuse entry of products

14 Design Controls Research Development Production Design Controls do not apply QSR Design Controls Apply

15 Foods = safe, wholesome, & sanitary Drugs Biologics Medical Devices } = safe and effective Cosmetic = safe Products labeled honestly and accurately Unsafe or unlawful products are removed employees facilities visited each year problem reports a year 25 cents of every consumer USD spent for FDA regulated products

16 Scientific, Regulatory, Public Health Agency Mission is to protect and promote public health Authority to regulate medical devices Federal FD&C Act Established regulatory controls for medical devices (May 28, 1976) 21 CFR Parts

17 Food Drugs Medical Devices * Biologics Animal Feed and Drugs Cosmetics Radiation-Emitting Products * Combination Products (drug-device*, biologic-device*, drug-biologic) Primary mode of action RFD (Request for Designation) Office of Regulatory Affairs (ORA) is the lead office for all field activities CDER Center for Drugs and Evaluation Research CVM Center for Veterinary Medicine * CDRH Center for Devices and Radiological Health FDA NCTR National Center for Toxicological Research CBER Center for Biologics and Evaluation Research CFSAN Center for Food Safety and Applied Nutrition

18 CDRH Center Director Dr. Daniel Schultz Office of Device Evaluation ODE Office of Compliance (OC) Office of Science and Engineering Laboratories (OSEL) Office of Surveillance and Biometrics (OSB) Office of Communication, Education and Radiation Programs (OCER) *International Affairs Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)

19 US FDA in general Structure of US FDA Importing to USA Recognized standards QSR Inspections Enforcement Some special questions

20 Legal import of MD into USA Section 801(a) (d) of the FD&C Act Subject to examination by FDA even if the product is authorized for marketing in another country Devices must be safe and effective Must contain informative and truthful labeling in English Imported products are required to meet the same standards as domestic goods Establishment Registration Medical Device Listing Compliant Labeling GMP/Quality Systems Appropriate marketing applications unless exempt 510(k) PMA Adverse Event Reporting, Records/Complaint Files

21 16 Classification Regulations 21 CFR (part ) Clinical chemistry and clinical toxicology Hematology and pathology Immunology and microbiology Anesthesiology Cardiovascular Dental Ear, nose and throat Gastroenterology & urology devices General and plastic surgery General hospital and personal use Neurological Ophthalmic Orthopedic and physical medicine Obstetrical and gynecological Radiology Medical Device Definition in Sec 201(h) of the FD&C Act

22 Risk-based Classification, level of reg control, and submission type 510(k) Exempt Class I Class II Class III Very low Low Medium High General Controls (may or may not be GMP exempt) General Controls Premarket Notification or 510(k) General & Special Controls 510(k) submission General & Special Controls Premarket Approval Level of risk and level of regulatory control

23 Two most common pathways to market in the U.S. Premarket Notification (PMN or 510(K)) Safety and effectiveness to a legally marketed (predicate) device through demonstration of substantial equivalence Class I, II, or III (pre-amendment) Traditional, Abbreviated, Special A successful submission results in FDA clearance Premarket Approval (PMA) Demonstration of safety and effectiveness (supported by clinical data) Class III (new, high risk devices and no predicate device, new indications) Traditional, Modular, PDP A successful submission results in FDA approval

24 Other pathways to market in the U.S. Humanitarian Device Exemptions (HDEs) Investigational Device Exemptions (IDEs), Amendments and Supplements Product Development Protocols (PDPs) RUO IUO De Novo Others

25 Pathways to market in the U.S. 510(k) 31 % of devices, review cost USD PMA 1% of devices, review cost USD Exempt 67% Other 1%

26 What are General Controls? Basic authorities that provide FDA with the means to regulate medical devices Applies to all medical devices regardless of classification, are subject to premarket and postmarket regulatory controls Establishment registration and device listing Premarket notification or 510(k), if not exempt Labeling Misbranding Adulteration Quality Systems Records and Reports/ Medical Device Reporting (MDR)

27 What are Special Controls? General controls alone are insufficient to assure safety and effectiveness of Class II/III devices Existing methods are available to provide such assurances Special controls may include special labeling requirements, mandatory performance standards and postmarket surveillance A few Class II devices are exempt from the premarket notification Postmarket Surveillance Study Patient Registries Guidelines (e.g., Glove Manual) Mandatory Performance Standard Recommendations or Other Actions Special Labeling (e.g., , Cranial Orthosis)

28 US FDA in general Structure of US FDA Importing to USA Recognized standards QSR Inspections Enforcement Some special questions

29 Consensus standards and guidance documents CDRH Standards Program Guidance Documents They are non-binding but very useful in streamlining the regulatory approval process

30 Role of consensus standards "Recognition and Use of Consensus Standards; Final Guidance for Industry and FDA" Conformance to standards is voluntary Alternate approaches allowed (less burdensome approach law), however, easier life if they are followed: safety and effectiveness easier to prove substantial equivalence easier to prove smaller amount of test data submitted/reviewed

31 Generic device standards, e.g. AAMI, ANSI, CEN, IEC, IEEE, ISO, UL: software medical device risk management human factors electrical safety electromagnetic compatibility

32 IVD specific standards e.g. Most NCCLS/CLSI standards: Automation and informatics Clinical chemistry and toxicology Evaluation protocols General laboratory practices Hematology Immunology and ligand assay Microbiology Molecular methods

33 US FDA Guidance and CLSI, e.g. EP5-A2 EP-7A EP-9A2 EP12-A EP-14A Evaluation of precision performance of clinical chemistry devices Interference testing in clinical chemistry Method comparison and bias estimation using patient samples User protocol for evaluation of qualitative test performance Evaluation of matrix effects

34 ISO vs. CLSI Complimentary not conflicting roles ISO provides broad standard requirements CLSI provides detailed best practices, standards and practical guidance for implementation ISO horizontal standards in principle CLSI vertical standards in practice

35 FDA websites

36 CDRH Databases Registration and Listing Premarket Approvals (PMA) Premarket Notifications (510(k)) Product Classification FDA-Recognized Consensus Standards MAUDE (Manufacturer and User Facility Device Experience) MDR (Medical Device Reporting) and others

37 Division of Small Manufacturers, International and Consumer Assistance (DSMICA) Fax (00) Phone (00) Write to us at: International Staff, Center for Devices and Radiological Health HFZ Piccard Drive Rockville, MD USA Device Advice (a self-service, interactive Site)

38 US FDA in general Structure of US FDA Importing to USA Recognized standards QSR Inspections Enforcement Some special questions

39 Regulated industry Consumer protection In control Shall be written Shall be followed

40 What is QSR? 21 CFR Part 820 CFR Code of Federal Regulations 21 Federal Food, Drug and Cosmetic Act Part 820 Quality System Regulation (QSR) ISO 13485:2003, but still ISO 9001 and QSR

41 QSR General provisions Quality system requirements Design controls Purchasing controls Identification and traceability Production and process controls Acceptance activities Non-conforming product Corrective and preventive action Labelling and packaging control Handling, storage, distribution and installation Records Servicing Statistical techniques

42 Quality Management System Design Controls Corrective & Preventive Actions Process and Production Controls Management Material Controls Records, Documents, & Change Controls Equipment & Facility Controls

43 Good Manufacturing Practice Federal Regulations CFR 21 Part 210, 211 CFR 21 Part 820 CFR 21 Part 803 CFR 21 Part 821 CFR 21 Part 806 CFR 21 Part 807 CFT 21 Part 312 CFR 21 Part 610 cgmp in manufacturing, processing, packing, holding, finished pharmaceuticals Quality system regulations Medical device reporting Medical device tracking requirements Medical device reports on corrections and removals Medical device registration and listing Investigational new drug application General biological products standards Interpretations: preambles, commissionaire s statements, guidelines, prejudicates (e.g. Warning letters)

44 US FDA in general Structure of US FDA Importing to USA Recognized standards QSR Inspections Enforcement Some special questions

45 US FDA Inspections Routine inspections For cause inspections Product sampling and testing Surveillance programs Undercover surveillance Consumer complaint follow-up MDRs Pre-approval History

46 The Investigator Basic investigator training Law and evidence development Investigative interviewing Medical device introductory course Certification Program Advanced speciality training Auditing for consistencyconsistency Prior Inspection Report Prior FDA-483 s Warning Letters and Responses MDR data bases Recalls 510(k) and PMA He or she will collect evidence! Guidance available to investigators Investigations Operations Manual (IOM) FD& C Act Compliance Program ( ) Design Control Guidance QSIT Handbook Other FDA Guidance

47 Quality System Inspection Technique Evaluate whether QS and subsystems are implemented effectively Management Controls Design Controls Corrective and Preventive Action Controls Production and Process Controls Minor: Facility and equipment controls Product controls Documents, records, change controls

48 US FDA: Regulatory enforcement Withhold approvals (premarket inspections) 483 Warning Letter License revocation/suspension Disbarment/disqualification Import detention/alert Obs! Only administrative decision! Recall Additionally in USA: Seizure destroy or recondition the product Injunction prevent the company or person from doing something Prosecution, jail Civil money penalty Against the company and responsible individuals Legal evidences needed

49 Same purpose, different punishment Whereas some evilly disposed persons That if any person shall sell any such diseased, corrupted, contagious or unwholesome provisions, whether for meat or drink, knowing the same without making it known to the buyer He shall be punished by fine, imprisonment, standing in the pillory Massachusetts, March 8, 1785

50 How can you prepare for an inspection? Create inspection routines with defined roles and prepared experts Training for the staff: rehearsals, general Learn the QSIT and Investigations operations manuals Mock inspection

51 Some easy pitfalls: how to avoid Understand the question Think through the question and your intended answer Answer the question concisely, directly, honestly Stick to the question; do not volunteer information Yes or no, if feasible Never guess, better I do not know Be prepared to have EVERYTHING scrutinized Exceptions that you do not need to give is financial information and quality management reviews minutes

52 RUO: For Research Use Only Products that are in the laboratory research phase of development, that is, either basic research or the initial search for potential clinical utility, and not represented as an effective IVD product Must be labeled For Research Use Only. Not for use in Diagnostic procedures No reporting of results Can be sold for profit

53 IUO: For investigational use only Product labeled: For Investigational Use Only. The performance characteristics of this product have not been established (according to 21 CFR (c)(2)(ii)). Products that are in the clinical investigation phase of development The safety and effectiveness of the product are being studied; i.e., the clinical performance characteristics and expected values are being determined in the intended patient population(s) The product cannot be used for human clinical diagnosis unless the diagnosis is confirmed by another, medically established diagnostic product or procedure

54 US FDA in general Structure of US FDA Importing to USA Recognized standards QSR Inspections Enforcement Some special questions

55 Some special questions Interstate Commerce Export from USA (lawful and unlawful devices; CFG) Lab developed tests RUO IUO ASR IVDMIA CLIA De Novo + much more

56 US FDA and product development US FDA and the rest of the world US FDA in general Design control in general (Design control elements)

57 All are linked to design control Design Controls Corrective & Preventive Actions Process and Production Controls Management Material Controls Records, Documents, & Change Controls Equipment & Facility Controls

58 Starting point Intended use Indications for use

59 Regulatory path? Class I, no submission required Class II, Premarket Notifications (510k) Class III, Premarket Approval Applications (PMA)

60 510(k), predicate, substantial equivalence Goal: to be found substantially equivalent to another device already legally marketed (predicate) All 510ks are based on the concept of substantial equivalence to a legally marketed device All 510ks provide a comparison between the device to be marketed and the predicate device(s)

61 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY/ASSAY-ONLY TEMPLATE A. 510(k) Number: B. Purpose for Submission: C. Measurand: D. Type of Test: E. Applicant: F. Proprietary and Established Names: G. Regulatory Information: 1. Regulation section: 2. Classification: 3. Product code: 4. Panel: H. Intended Use: 1. Intended use(s), 2.Indications for use: 3. Special conditions for use statement(s): 4. Special instrument requirements: I. Device Description: J. Substantial Equivalence Information: K. Standard/Guidance Document Referenced (if applicable): L. Test Principle: M. Performance Characteristics: 1. Analytical performance: a. Precision/Reproducibility: b. Linearity/assay reportable range: c. Traceability, Stability,(controls, calibrators, methods): d. Detection limit: e. Analytical specificity: f. Assay cut-off: 2. Comparison studies: a. Method comparison with predicate device: b. Matrix comparison: 3. Clinical studies: a. Clinical Sensitivity: b. Clinical specificity:

62 Analytical Performance Characteristics 1. Analytical performance: a. Precision/Reproducibility b. Linearity and assay reportable range c. Traceability, Stability d. Detection limit e. Analytical specificity f. Assay cut-off 2. Comparison studies: a. Method comparison with predicate device b. Matrix comparison

63 Design Control Elements Design Input Design Review Design Output Design Verification Design Validation Design Change Design Transfer

64 Design Input Make certain that the design requirements relating to a device are appropriate and address the intended use of the device, including the needs of the user and patient (User requirements transformed into design requirements) Shipping containers are designed and constructed to protect the device Design of the content and physical parameters of labeling The input procedures shall address incomplete, ambiguous, or conflicting requirements Results in specifications linked to the user requirements

65 Design Input Identify device requirements during the design input phase or beginning of the design activity Design input includes determining customer needs, expectations and requirements plus determining regulatory, standards, and other appropriate requirements 1. What is the real need for the new device? 2. Where will the new device be used? 3. Who will use the new device? 4. How will the new device be used? 5. With what devices will the new device be used? 6. How long will the new device be used? 7. Other questions related to the specific device to be developed?

66 Design Input: OLEELLINEN VAIHE!!! Riittävä panostus prosessiin user requirements design specifications Koko projektin tärkeimpiä asioita!!! Specifications thoroughly reviewed and approved before physical design and development begins To establish complete device requirements and specifications that will minimize subsequent changes Design output shall meet design input!

67 Design Output Must be stated in a verifiable manner Must always meet design inputs and thus user requirements Must give information for purchasing and production Must contain acceptance criteria and process information (e.g. description, critical points, validation needs)

68 Design Transfer Ensure that the device design is correctly translated into production specifications Design transfer should assure that the section of the design being transferred: meets input requirements contains acceptance criteria, where needed contains design parameters which have been appropriately verified is complete and approved for use is fully documented in the DMR or contains sufficient design output information to support the generation of remaining DMR documents is placed under change control if not already done

69 Logically related documents Design History File DHF Development information OUTPUT Device Master Record DMR Build information Device Master Record = keittokirja Device History Record DHR Serial Number Information Device History Record DHR Serial Number Information Device History Record DHR Serial Number Information Device History Record DHR Serial Number Information Device History Record DHR Serial Number Information