1. Regulatory Issues

2. Introduction to the Regulatory Approval Process; Overview of the FDA Investigational New Drug Application (IND); Summary of regulations and guidelines Introduction of cGMP's/principles of validation Introduction to QA/QC principles Good Laboratory Practice (GLP) compliance Pre-clinical testing for biotechnology products; safety and toxicology Clinical stages, design of clinical trials and protocols, evaluation of clinical data Regulatory Filings: Biological License Application (BLA) Pre-approval inspections Team Biologics International regulatory status for biotechnology products; WHO, Japan, and the EC/CPMP application International Conference on Harmonization (ICH) update Regulatory considerations for gene therapy and transgenic products

3. FDA Structure / Organization Center for Veterinary Devices Food and Drug Administration Center for Biologics Evaluation and Research Center for Devices and Radiological Health National Center for Toxicological Research Center for Food Safety and Applied Nutrition Center for Drug Evaluation and Research FDA Structure / Organization Office of CombinationProducts

4. Office of Device Evaluation Office of In-Vitro Diagnostic Devices & Safety Office of Health & Industry Programs Office of Science & Technology OfficeofCompliance Office of Surveillance & Biometrics Center for Devices and Radiological Health CDRH Offices

5. FDA's Three Key Development Roles: "Gatekeeper" to the marketplace -- the new drug approval process "Cop on the beat" or "Enforcer" -- ensuring quality compliance via inspection and enforcement actions (e.g. criminal charges) "Sentinel" of Safety Concerns - during development and post-approval

6. 6 FDA regulation of medical products Among the products that FDA regulates are three categories of diagnostic, preventative, or therapeutic products: – Drugs – Biologics – Medical devices

7. The Approval Gate … Preliminary Considerations -- Determining the Regulatory Status of the product – Is it a "drug", "device" or "biologic"? Drug: – described in USP ( United States Pharmacopeia) or – intended (via labeling) » to affect the body of man or other animals » to be used in the diagnosis, cure, mitigation, treatment or prevention of disease in man or other animals

8. The Approval Gate … Regulatory Status of the product - con'd… – Is it a "drug", "device" or "biologic"? Device: defined as involving: "instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or "similar or related article including any component, part or accessory." – in USP/NF (the National Formulary) or – intended to be used in diagnosis … cure, mitigation, treatment or prevention of disease or other conditions – intended to affect the body of man

9. The Approval Gate … Regulatory Status of the product - con'd… – Is it a "drug", "device" or "biologic"? Thus -- device definition can capture products that resemble drugs if they do not achieve their result via being metabolized in the body or via chemical action within or on the body -- regulated by FDA Center for Devices & Radiological Health (CDRH) – Examples of "drug-like" devices: » Ultrasound contrast media » Contact lens solutions

10. The Approval Gate … Regulatory Status of the product - con'd… – Is it a "drug", "device" or "biologic"? Biologic -- – Generally, if derived from human or animal tissue; – used to be regulated by FDA Center for Biologics (CBER) using approval standards similar to CDER – therapeutic biotech products going to CDER » vaccines – remain behind NOTE: "true" biotech products usually are biologics

11. The Approval Gate … Regulatory Status of the product - con'd… – Is it a "drug", "device" or "biologic"? – OR BOTH?? – "Combination" or "hybrid" products -- are regulated per their "primary mode of action" -- but this may be difficult to discern -- get clarification very early as will impact FDA Center you deal with can request in writing -- under FDAMA § 416, FDA can't later change its mind w/o your consent or public health reasons exist

12. The Approval Gate … Regulatory Status of the product - con'd… – What type of submission is needed to get FDA approval or clearance? – Drugs: Full New Drug Application (NDA) 505(b)(2) NDA or "Paper NDA" Abbreviated New Drug Application The OTC Drug route -- Abreva (Avanir/SKB) – NDA – OTC Review monograph change

13. The Approval Gate … Regulatory Status of the product - con'd… – What type of submission is needed to get FDA approval or clearance? – Devices: Premarket Approval Application (PMA) -- clinical studies will be needed Premarket Notification under § 510k -- clinical studies MAY be needed (or wanted)

14. The Approval Gate … Regulatory Status of the product - con'd… – What type of submission is needed to get FDA approval or clearance? – Biologics Biologic License Application (BLA) no generic versions now possible – may change …

15. The Approval Gate … Regulatory Status of the product - con'd… – What quantity and quality of data will be demanded by FDA to show safety & effectiveness? – Will vary -- FDA has extensive discretion here – Key task -- try to get clarity as soon as possible in the process -- Ways to do so: Pre-IND meeting -- encouraged by FDA prior to start of human clinicals End of Phase 2 Meeting - also encouraged -- here's where you want to "lock" them in

16. Overview of Typical Pharmaceutical Product Development 16 PreClinical Work Clinical Studies Registration Validation Commercial Production FILINGFILING APPROVALAPPROVAL VALIDATIONVALIDATION IP Marketing Research Marketing Plan 1 In 2000 Dollars - Estimates by the National Cancer Institute for all new pharmaceutical. Estimate does not consider R&D costs that are not associated with the development of the drug in question. Most drug companies use a system of cost estimates that includes the valuation of money if it had been invested andthe cost of drug development not approved by the FDA. Most studies conclude that the rate of commercialization success to be 1:5000. How Much does it cost to develop a new drug - James Love Consumer Project on Technology http://www.cptech.org April 2, 2000http://www.cptech.org 2 Drug Approval Overregulation, MR Ward - CATO Regulation - http://www.cato.org/pubs/regulation/reg15n4e.htmhttp://www.cato.org/pubs/regulation/reg15n4e.htm 3 New York Times - November 8 1995 Cost: 1 Preclinical to Phase II - Approximately 1-7 million Phase III - 2 - 8 million Time: 2,3 Validation Batches - Product Costs and Labor X 3 to 5 batches Production Start Up Costs based on Contract or Facility Total Costs = 10-25 million USD Preclinical to Completed Clinicals - 3-5 years FDA Approval - 13.5 months 3 Validation and Production Launch - 6-18 months Total Time = 4.5 - 7.5 years Product Launch

17. Welcome to the Jungle 17 Pre Clinical Work Clinical Trials Registration Validation Registration Validation Commercial Production Commercial Production Filing Approval Pre Approval Inspection Stability Stable Unstable FAIL GO Animal Effective Ineffective FAIL GO Toxicology Safe Toxic FAIL GO Micro Antimicrobial & Aseptic Grows Bugs FAIL GO Chemistry Passes ID & Description Degradants & Impurities FAIL GO Reformulation Egg START OVER Reformulation Egg START OVER REFORMULATE Death of Product Phase I Phase I Proof of Concept Phase II Phase II Efficacy Phase III Phase III Definition FAIL Ineffective Effective GO FAIL Ineffective Inferior Effective GO Tweak Formula Re-Evaluate FAIL Ineffective Effective GO Clinical Report Failure is Unlikely Min. Energy Batch Max. Energy Batch Nominal Batch Nominal Batch FAIL GO FAIL GO PASS GO PASS Reset Parameters Reset Parameters RESET ALL PARAMETERS Quarantine Product Scale Up Production Scale Up Production Launch Ad Campaign Launch Ad Campaign Fill Sales & Warehouse Pipeline Fill Sales & Warehouse Pipeline Launch Validation Report Stability Testing Sell Product Validation Sign Off Phase IV Phase IV FDA STUDIES Formula Improvement Geriatric or Pediatric Drug Interaction Define LT & Side Effects

18. And the next step… You’ve got the device or drug okayed—now you have to manufacture it…

19. 19 GMPs Current good manufacturing practices (GMPs) are the methods by which manufacturers, holders, and transporters of drugs, biologics, or devices assure that every product that they make, hold, or transport is, and continues to be until it is used, safe and effective. Failure to comply with GMPs (and for devices, failure to comply with the quality system regulations) makes a product “adulterated” and its distribution or sale illegal.

20. The Early Beginnings 1900s house-calls Home remedies, ointments and “miracle elixirs” Entertainment and music No regulations until 1902 Fig. 1. Animation of ancient medicine show

21. Public Involvement 1905 - The Jungle by Upton Sinclair Exposure of unsanitary conditions in meat packing plants Public awareness and involvement Pure Food and Drug Act False labeling became illegal Fig. 2. The Jungle by Upton Sinclair Fig. 3. 1906 Meat processing plant

22. What is GMP? Good Manufacturing Practice is a set of regulations, codes, and guidelines for the manufacture of drug substances and drug products, medical devices, in vivo and in vitro diagnostic products, and foods. Fig.4 GMP handbooks for every industry

23. Good Manufacturing Practices Worldwide Enforcement Good Manufacturing Practices are enforced in the United States by the FDA In the United Kingdom by the Medicines and Healthcare Products Regulatory Agency GMPs are enforced in Australia by the Therapeutically Goods Administration In India by the Ministry of Health, multinational and/or foreign enterprises Many underdeveloped countries lack GMPs

24. 1941 Initiation of GMP Sulfathiaziole tablets contaminated with phenobarbital 1941 - 300 people died/injured FDA to enforce and revise manufacturing and quality control requirements 1941 - GMP is born Fig. 5 1906 Certificate of Purity signed by doctor

25. 1962 Kefauver-Harris Drug Amendments Thalidomide tragedy Thousands of children born with birth defects due to adverse drug reactions of morning sickness pill taken by mothers Strengthen FDA’s regulations regarding experimentation on humans and proposed new way how drugs are approved and regulated “Proof of efficacy” law

26. 1976 Medical Device Amendments 1972 and 1973 -Pacemaker failures reported 1975 - hearing-Dalkon Shield intrauterine device caused thousands of injuries Class I, II and III medical devices – based on degree of control necessary to be safe and effective Fig.7 President Gerald Ford signs the Medical Device Amendments

27. 1980 Infant Formula Act 1978 - major manufacturer of infant formula reformulated two of its soy products 1979 - Infants diagnosed with hypochloremic metabolic alkalosis Greater regulatory control over the formulation and production of infant formula Modification of industry’s and FDA’s recall procedures Fig.8 Parody on Infant Formula Act

29. Part 211 –Selected cGMP For Finished Pharmaceuticals Subpart A-General Provisions Subpart B-Organization and Personnel 211.22 Responsibilities of quality control unit. 211.25 Personnel Qualifications. 211.28 Personnel responsibilities. Subpart C-Buildings and Facilities 211.46 Ventilation, air filtration, air heating and cooling. 211.58 Maintenance Subpart D-Equipment 211.63 Equipment design, size, and location. 211.65 Equipment construction. 211.67 Equipment cleaning and maintenance. 211.68 Automatic, mechanical, and electronic equipment. 211.72 Filters. Subpart E-Control of Components and Drug Product Containers and Closures 211.80 General requirements. 211.82 Receipt and storage of untested components, drug product containers, and closures. 211.84 Testing and approval or rejection of components, drug product containers, and closures. 211.86 Use of approved components, drug product containers, and closures. Subpart F-Production and Process Controls 211.100 Written procedures; deviations. 211.101 Charge-in of components. 211.103 Calculation of yield. 211.105 Equipment identification...............

30. § 211.25 Personnel qualifications (a) Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee's functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them. (b) Each person responsible for supervising the manufacture, processing, packing, or holding of a drug product shall have the education, training, and experience, or any combination thereof, to perform assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess. (c) There shall be an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each drug product.

31. Quality Assurance vs. Quality Control Quality Assurance An overall management plan to guarantee the integrity of data (The “system”) Quality Control A series of analytical measurements used to assess the quality of the analytical data (The “tools”)

32. True Value vs. Measured Value True Value The known, accepted value of a quantifiable property Measured Value The result of an individual’s measurement of a quantifiable property

33. Accuracy vs. Precision Accuracy How well a measurement agrees with an accepted valuePrecision How well a series of measurements agree with each other

34. Systematic vs. Random Errors Systematic Error Avoidable error due to controllable variables in a measurement. Random Errors Unavoidable errors that are always present in any measurement. Impossible to eliminate

35. Quality Control Measures Standards and Calibration Blanks Recovery Studies Precision and Accuracy Studies Method Detection Limits State Laws

36. Standards and Calibration Prepared vs. Purchased Standard Signals: Peak Area, Beer’s Law Calibration Curves Continuing Calibration Checks Internal Standards Performance Testing

37. Calibration Curves Graphical representation of the relationship between: The analytical signal The concentration of the analyte and

39. Continuing Calibration Verification Many methods don’t require that daily calibration curves are prepared A “calibration verification” is analyzed with each batch of samples

40. Sample Batch 10 - 20 samples (method defined) or less Same matrix Same sample prep and analysis Contains a full set of QC samples

41. Internal Standards A compound chemically similar to the analyte Not expected to be present in the sample Cannot interfere in the analysis Added to the calibration standards and to the samples in identical amounts

42. Internal Standards Refines the calibration process Analytical signals for calibration standards are compared to those for internal standards Eliminates differences in random and systematic errors between samples and standards

43. Performance Testing Blind samples submitted to laboratories ? ? ? Labs must periodically analyze with acceptable results in order to maintain accreditation

44. Blanks, Blanks, Blanks Laboratory Reagent Blanks Instrument Blanks Field Reagent Blanks Trip Blanks

45. Laboratory Reagent Blanks Contains every reagent used in the analysis Is subjected to all analytical procedures Must give signal below detection limit Most methods require one with every batch

46. Instrument Blank A clean sample (e.g., distilled water) processed through the instrumental steps of the measurement process; used to determine instrument contamination

47. Field Reagent Blanks Prepared in the lab, taken to the field Opened at the sampling site, exposed to sampling equipment, returned to the lab.

48. Trip Blanks Prepared in the lab, taken to the field Not opened Returned to the lab Not always required in EPA methods

49. Recovery Studies Matrix Spikes Laboratory Control Samples Surrogates

50. Matrix Spikes Sample spiked with a known amount of analyte Subjected to all sample prep and analytical procedures Determines the effect of the matrix on analyte recovery Normally one per batch

51. Laboratory Control Sample Subjected to all sample prep and analytical procedures Analyte spiked into reagent water

52. Precision and Accuracy Required for initial certification and annually thereafter A series of four laboratory control samples Must meet accuracy (recovery) and precision (standard deviation) requirements, often in method

53. Method Detection Lim it “The minimum concentration of a substance that can be measured and reported with 99% confidence that the analyte concentration is greater than zero”

54. Method Detection Limit MDLs are determined according to 40 CFR, part 136, Appendix B Seven replicate laboratory control samples, analyzed for precision

55. Method Detection Limit Must be performed initially for certification Must meet criteria specified in method Must be performed with change in instrumentation or test method Annually with ELCP (Environmental Laboratory Certification Program)

56. State Laws Each state has laws governing laboratories and their personnel.