1. FDA/Health Canada Seminar 20 February 2003 Initial Product Development Process Martha A. Feldman, RAC Drug & Device Development Co., Inc. P.O. Box 3515 Redmond, WA 98073-3515 USA 1-425-861-8262 FAX: 1-425-869-5854 mfeldman@druganddevice.com

2. FDA/Health Canada Seminar 20 February 2003 Drugs and Biotechnologically- Derived Products

3. FDA/Health Canada Seminar 20 February 2003 Overview of Product Development Process for Drugs/Biologics Product concept Product requirements Product specifications: formulation Testing: bench, animal Initial submissions Human testing (Phases 1, 2 and 3; Post-marketing) Pilot plant - scale up - manufacturing Quality Assurance: clinical, manufacturing Submissions

4. FDA/Health Canada Seminar 20 February 2003 Product Concept Drug substance: an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body A“biologic product”: any virus, therapeutic serum, toxin, antitoxin or analogous product applicable to the prevention, treatment or cure of diseases or injuries of man

5. FDA/Health Canada Seminar 20 February 2003 Product Concept Ideas come from: consumers, healthcare practitioners, academia, pharmacists, serendipitous findings (e.g., Merck - Timoptic) May be entirely new product, modification of existing product, new use for existing product (e.g., Thalidomide)

6. FDA/Health Canada Seminar 20 February 2003 Product Requirements What product will do: –Diagnose disease; cure disease; mitigate disease; treat disease, injuries; prevent disease, injuries; affect structure or function of human body To what patient population To what degree With what amount of risk Over what time At what cost: to consumer; to manufacturer

7. FDA/Health Canada Seminar 20 February 2003 Product Specifications Strength, potency Purity Dosage(s) Route(s) of administration Formulation Stability Toxicity

8. FDA/Health Canada Seminar 20 February 2003 Bench Testing Chemical characterization: name, chemical formula, structural formula, etc. Physical properties: molecular weight, odor, color, polarity, boiling point, etc.

9. FDA/Health Canada Seminar 20 February 2003 Animal Testing Testing depends on intended duration of use, route of administration target population Pharmacological profile –pharmacokinetics –dose ranging Toxicology –standard tests (ADME, pharmacodynamics) –additional tests (e.g., mutagenicity)

10. FDA/Health Canada Seminar 20 February 2003 Animal Testing Efficacy testing –need to have validated animal model for disease, clinical condition –duration of testing depends on proposed duration of human dosing route of administration stage of product development

11. FDA/Health Canada Seminar 20 February 2003 Clinical Testing If there are any reports of prior use in humans, can use to plan further studies –same or other indications, dosages, populations –can develop safety profile Overall Investigation Plan –Phase 1: usually normals; safety, dose ranging –Phase 2: first use in patients; early efficacy info –Phase 3: wide use; multicenter

12. FDA/Health Canada Seminar 20 February 2003 Initial FDA Submission Investigational New Drug (IND) Application (21 CFR Part 312) - permission to ship drug for the purpose of testing in humans; request for exemption of laws prohibiting interstate shipment of unapproved drugs or biological products IND is amended (updated) with each phase of the clinical investigation

13. FDA/Health Canada Seminar 20 February 2003 IND Contents - 1 (21 CFR 312.23) Cover sheet Table of contents Introductory statement and general investigational plan: –rationale –indications for use –clinical study plans for first year –number of patients –known possible risks

14. FDA/Health Canada Seminar 20 February 2003 IND Contents - 2 Investigator’s Brochure –chemical and physical information on drug –summary of animal toxicology and pharmacology –summary of pharmacokinetics and ADME –summary of safety and efficacy from prior human studies, if any –summary of possible risks

15. FDA/Health Canada Seminar 20 February 2003 IND Contents - 3 Protocols –one for each study –Phase 1: more flexible, less detailed than Phases 2, 3 –general contents objectives and purpose names and qualifications of investigators; facility address; IRB information patient selection criteria; number of subjects study design; controls to be used dosages chosen and why; duration of treatment description of observations, clinical procedures

16. FDA/Health Canada Seminar 20 February 2003 IND Contents - 4 Chemistry, Manufacture and Controls –for both the drug substance and drug product –methods to ensure identification,quality, purity, strength –methods of preparation of dosage form and amount –update as clinical studies proceed from Phase 1 to 3 (i.e., pilot plant, scale-up, full GMP manufacturing) –labeling –environmental analysis, or exclusion

17. FDA/Health Canada Seminar 20 February 2003 IND Contents - 5 Pharmacology and Toxicology –data on which the sponsor feels it is safe to proceed with human studies; qualifications of those deciding –animal and in vitro studies –pharmacology and drug disposition (ADME) –toxicology acute subacute chronic

18. FDA/Health Canada Seminar 20 February 2003 IND Contents - 6 Previous human experience –safety profile –efficacy data if studied under controlled conditions –where marketed, or withdrawn from market Additional information –dependency potential –radioactive drugs –pediatric studies Relevant information (if requested by the FDA)

19. FDA/Health Canada Seminar 20 February 2003 Medical Devices

20. FDA/Health Canada Seminar 20 February 2003 Overview of Product Development Process for Medical Devices Product concept Product requirements Product specifications: components Classification of medical device Testing: bench, animal, human (may need initial submission for Class III product) Pilot plant - scale up - manufacturing Quality Assurance: clinical, manufacturing Submissions

21. FDA/Health Canada Seminar 20 February 2003 Product Concept "an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent...including a component part, or accessory which is:  recognized in the National Formulary, or the U.S. Pharmacopoeia,  intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, or  intended to affect the structure or any function of the body...and which does not achieve any of it's primary intended purposes through chemical action within or on the body ….. and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes."

22. FDA/Health Canada Seminar 20 February 2003 Product Concept Ideas come from: consumers, healthcare practitioners, academia,engineers, May be entirely new product, modification of existing product (e.g., ultrasound for metal fatigue testing), new use for existing product (e.g., ultrasound to cause cavitation to help dissolve clots)

23. FDA/Health Canada Seminar 20 February 2003 Product Requirements - 1 performance for intended use operating conditions, e.g., temperature, humidity, altitude limits reliability durability; robustness stability; shelf life biocompatibility ergonomics, e.g., ease of use

24. FDA/Health Canada Seminar 20 February 2003 Product Requirements - 2 sterility electromagnetic compatibility radio frequency interference cost of components complexity of manufacturing process environmental assessment –manufacturing process –disposal issues

25. FDA/Health Canada Seminar 20 February 2003 Product Specifications Performance ranges in intended population(s); tolerances Ease of use; training requirements (especially for home use devices) Safety of patients, of operator Sterilization, (and resterilization if needed)

26. FDA/Health Canada Seminar 20 February 2003 Human Factors Engineering Guidance Documents: –Do it by Design: An Introduction of Human Factors into Medical Devices (Dec. 1996) http://www.fda.gov/cdrh/humfac/doitpdf.pdf –Medical Device Use-Safety: Incorporating Human Factors Engineering into Risk Management, July 18, 2000 http://www.fda.gov/cdrh/humfac/1497.pdf

27. FDA/Health Canada Seminar 20 February 2003 Classification of Medical Devices Class 1: General Controls Class 2: General controls and performance standards Class 3: General controls, performance standards, clinical studies to demonstrate safety and effectiveness

28. FDA/Health Canada Seminar 20 February 2003 Bench Testing Type of testing depends on product –electromagnetic compatibility –radio frequency interference –electrical leakage –power output –material strength, flexibility, durability, etc. –sterility –reliability

29. FDA/Health Canada Seminar 20 February 2003 Animal Testing Biocompatibility –type, duration of testing dependent upon human exposure, e.g., permanent/long-term implant versus one-time/ short use Effectiveness –animal model available for disease, clinical condition –parameters to be measured comparable to human condition (e.g., pig heart valve)

30. FDA/Health Canada Seminar 20 February 2003 Clinical Testing - 1 Clinical testing not always required Feasibility test; proof of concept: –3-5 subjects –one site –usually investigator-sponsored Pilot test protocol –10-30 subjects –one or two sites –“test drives” protocol and operator’s manual

31. FDA/Health Canada Seminar 20 February 2003 Clinical Testing - 2 Pivotal Study –consult guidance document, if any (may be on type of product or disease/clinical condition) –number of subjects varies experiential study confirmatory study statistically significant –multiple sites –duration depends on human exposure to device

32. FDA/Health Canada Seminar 20 February 2003 Initial FDA Submission May need only IRB approval to proceed with study on non-significant risk device, i.e., no prior FDA approval to conduct study Investigational Device Exemption (IDE) needed for significant risk device or condition of use IDE may be needed for studies on Class II (510K) or Class III (PMA) products

33. FDA/Health Canada Seminar 20 February 2003 IDE Contents - 1 (21 CFR 812.20) Cover sheet Table of contents Report of prior investigations Investigational plan Methods, facilities and controls for manufacturing, packaging, storing, installation Example of Investigator Agreements Certification of Investigator Agreement

34. FDA/Health Canada Seminar 20 February 2003 IDE Contents - 2 IRB information Other institutions studying the device that are not listed above Sale or charges for investigational device –why not considered commercialization Environmental assessment –or request for categorical exclusion

35. FDA/Health Canada Seminar 20 February 2003 IDE Contents - 3 Labeling –labels –instructions for use; operator’s manual Informed consent documents Other relevant information, as requested by FDA

36. FDA/Health Canada Seminar 20 February 2003 Investigational Plan (21 CFR 812.25) Name and intended use of the device Objectives and duration of the investigation Protocol Risk analysis Device description Monitoring procedures Labeling Consent materials IRB information Other institutions Additional records and reports

37. FDA/Health Canada Seminar 20 February 2003 Premarket Notification The official means of providing the FDA with information regarding safety & effectiveness The “510(K)” - named after that section of the Food, Drug & Cosmetic Act. It demonstrates that the device is “substantially equivalent” to a device legally on the market Once submitted, FDA has to make an SE determination within 90 days of receipt FDA “clears” the device for marketing.

38. FDA/Health Canada Seminar 20 February 2003 Premarket Notification (510[K]) When a 510(K) is required –marketing of new devices –first time marketing of devices –importing device into US for first time –significant change or modification to a device major material supplier, design change, new facility –change in labeling new indication, new population

39. FDA/Health Canada Seminar 20 February 2003 Exemptions from filing a 510(K) Already in commercial distribution before May 28, 1976 Custom devices –for one patient under prescription –for one practitioner for use in his/her practice (e.g., surgical instrument for surgeon with missing fingers) Distributors and repackagers –who only adds name to the device Class I medical devices (as of Feb 19, 1998)

40. FDA/Health Canada Seminar 20 February 2003 The “510(K)” - contents (21 CFR 807.87) device name (trade, common, classification) establishment registration number device class compliance with performance standards proposed labels, labeling, advertisements –intended use, instructions for use predicate comparison

41. FDA/Health Canada Seminar 20 February 2003 510(K) Contents - 2 for a modified or new device, state effect of change on safety and effectiveness profile of original product summary or statement (21 CFR 807.92) financial certification or disclosure for SE to a reclassified Class III device, list of S&E issues

42. FDA/Health Canada Seminar 20 February 2003 510(K) Contents - 3 statement of truthfulness of contents any additional information requested by the FDA

43. FDA/Health Canada Seminar 20 February 2003 In Vitro Diagnostic Devices

44. FDA/Health Canada Seminar 20 February 2003 Overview of Product Development Process for In Vitro Diagnostics Product concept Product requirements Product specifications: reagents, analytes, antibodies Classification of medical device Testing: bench, human (rarely need initial submission for human studies) Pilot plant - scale up - manufacturing Quality Assurance: clinical, manufacturing Submissions

45. FDA/Health Canada Seminar 20 February 2003 Product Concept - 1 In vitro diagnostic products are those reagents, instruments, and systems intended for use in the diagnosis of disease, or other conditions, including a determination of the state of health, in order to cure, mitigate, treat or prevent disease or its sequelae. Such products are intended for use in the collection, preparation and examination of specimens taken from the human body.

46. FDA/Health Canada Seminar 20 February 2003 Product Concept - 2 screening diagnosis monitoring prognosis prevention

47. FDA/Health Canada Seminar 20 February 2003 Product Requirements Sensitivity and specificity Accuracy and precision Rapidity of results Linearity Reproducibility: operator and unit Built-in quality control Small amount of specimen needed Stability of reagents

48. FDA/Health Canada Seminar 20 February 2003 Product Specifications Examples: –sensitivity and specificity –upper and lower limits of detection –limited number of interfering substances –rapidity of obtaining results –robust –if for home use or physician office use, then ease and simplicity of use

49. FDA/Health Canada Seminar 20 February 2003 Bench Testing fresh/frozen samples; freeze-thaw of samples; shelf-life of samples inter- and intraoperator reproducibility inter- and intradevice reproducibility linearity, especially at “cross-over” point interfering substances stability of reagents, other components

50. FDA/Health Canada Seminar 20 February 2003 Clinical Testing Check for guidance documents Need Institutional Review Board approval (more for privacy issues than for safety) Prospective usually; retrospectively collected samples allowed in some cases Protocol conducted at minimum of three sites Special testing requirements for home use Clinical Laboratory Improvement Act (CLIA)

51. FDA/Health Canada Seminar 20 February 2003 Initial FDA Submission Premarket Notification (PMN) - also known as 510(K) after the section of the FD&C Act May or may not require prospective human testing Retrospective clinical studies may or may not require IRB approval - depends on privacy issues

52. FDA/Health Canada Seminar 20 February 2003 Contents of a 510(K) for IVDs Same as for other medical devices Additional requirements for home use –testing –labeling/instructions for us “Safety” may also be tied to false negative results

53. FDA/Health Canada Seminar 20 February 2003 Specific references for IVDs In Vitro Diagnostic Devices: Guidance for the preparation of 510(K) submissions, Jan., 1997 http://www.fda.gov/cdrh/manual/ivdmanul.html Guidance for FDA Staff: Regulating In Vitro Diagnostic (IVD) Device Studies http://www.fda.gov/cdrh/comp/ivdreg.html (Dec. 17, 1999)Over-the-Counter in vitro diagnostic devices, (April 19, 2002) http://www.fda.gov/cdrh/ode/otclist.html

54. FDA/Health Canada Seminar 20 February 2003 References FDA web page –www.fda.gov Code of Federal Regulations Title 21 –Part 312 Drugs and biologics –Part 807 Premarket Notifications (510K) –Part 812 Investigational Device Exemptions

55. FDA/Health Canada Seminar 20 February 2003 More References ISO IEC, CEN - electromechanical devices AAMI, BSI, CSA, etc. - standards organizations UL - electrical leakage