1. Regulatory Issues US and Abroad BIT 230 Chapters 9-11 Huxsoll

2. Regulatory Affairs Separate discipline that is part of product development team Know laws enforced by FDA Certain area of FDA presides over your product Liaison between company and government - CSO (Consumer Safety Officer)- point person from FDA

3. FDA Review - law enforcement agency charged with the health and safety of food, drugs, cosmetics, medical devices Division  CDER - drugs  CBER - biologics  CDRH - devices/radiologic health  CVM - veterinary medicine  CFSAN - food safety and applied nutrition

4. FDA SAFETY and efficacy

5. FDA Burden of proof for safety and efficacy evidence from product sponsor FDA decides if there is enough evidence to approve product needs ‘substantial evidence” (between preponderance of evidence and beyond a reasonable doubt) rules often reactive to a crisis

6. FDA activities Rulemaking - formulating, amending or repealing a rule  disseminating info. To public Adjudication - agency process for the formulation of an order (telling someone what to do  responds to sponsor’s application for approval to the FDA

7. Guidelines & Points to Consider Guidelines - procedures and standards acceptable to the FDA  communicate info that FDA has vast experience Points to Consider -  areas where FDA has little experience Guidelines and PtC not enforceable requirements (like other aspects of FDA)

8. Product Characterization See pages 142-143 -product definitions Drug  cure, diagnose, treat prevent Device  instrument, apparatus, machine, implant, reagent Biological product  virus, serum, toxin, vaccine, blood product

9. Regulatory functions Submissions Compliance Enforcement Miscellaneous

10. Submission File application with the FDA NDA - new drug application - product not yet recognized as safe and effective Devices - Class O, II, III; I and II need a Premarket Notification- 90 day notice before goes into market; Class III needs FDA approval before commercial marketing begins

11. Submission cont’d Biological products - requirements special PLA - product license application, to describe the product ELA - establishment license application -to describe the facilities used to manufacture the product

12. Submission cont’d Remember three areas:  premarketing (IND)  marketing (NDA)  postmarketing (after on the market)

13. Compliance GLP  nonclinical laboratory studies GMP  set of rules for drugs, medical devices and biologics GCP  inform subjects of test product in clinical trials

14. Other compliance areas Study/data audits  review raw data in reports corporate policies and procedures  self-imposed procedures for compliance submissions commitments  especially to coordinate manufacturing facilities in different countries

15. Compliance 3 key points:  documentation

16. Enforcement Civil or criminal penalties Product liability suits From Huxsoll page 147:  “ Enforcement is the end result of a lack of integration. It implies a failure in the systems designated to prevent mistakes and inadvertent or untested changes.”

17. Miscellaneous State requirements for compliance (in addition to federal) e.g in book- California State Board of Pharmacy says pharmacist responsible for manufacturing State and federal laws for controlled substances Incentives for orphan products

18. European Regulatory Issues Chapter 10

19. One Europe 1995 “mutual regulation” for drug regulation by EU members European Medicines Evaluation Agency (EMEA) - administering centralized procedure Submit to agency and can get simultaneous approval in many European countries (for highly innovative products)

20. Other Products Conventional products - submit filing to country of choice Once approved there, other members of the EU will recognize the drug’s registration Send to central agency only if concerns about original registration in Europe

21. European Drug Market Small continent in comparison to some others, but one of largest drug markets outside the US (total population of Europe estimated at 400 million, down from # in textbook of close to 700 million) Uses many medicines Approval may be faster in Europe RU 486 example

22. EC 1957 European Economic Community France, Germany, Belgium, Italy, Luxembourg and Netherlands Formed to achieve harmonization of laws and regulations for bringing drugs to market

23. Special organizations Concertation procedure, for marketing products  Recombinant DNA products  transformed lines  hybridoma and monoclonal antibody procedures  Referred to the CPMP (Committee for Proprietary Medicinal Products)

24. Approval Europe faster approval time lines than US (although not much; 417 vs. 452 days for US For recombinant products, 411 in Europe vs. 548 days for approval in US’ FDA faster than EMEA on monoclonal antibody approval

25. Approvals cont’d EMEA doesn’t have priority review like FDA does; may try and implement such a review See and review handout from Tufts about EU/EMEA summary

26. Regulatory Issues in Japan Chapter 11

27. The Ministry of Health & Welfare Oversees social welfare, social security and public health in Japan Made up of several bureaus, local branches and affiliations PAB(Pharmaceutical Affairs Bureau) one of bureau for drugs Page 174 - chart (DO NOT need to know!)

28. PAB Supervises domestic & foreign drug- related products Director General of the PAB similar to head of FDA 8 divisions within PAB to deal with various aspects (biologics & antibiotics, safety, etc.) Many functions similar to US (fee page 175)

29. CPAC Central Pharmaceutical Affairs Council Powerful agency within ministry Government advisory committee Makes recommendation for final approval for drug manufacturing and importation of foreign drugs

30. Standards for Production Japan has GLP, GMP and GCP regulations for GCP, has guidelines for 14 therapeutic areas (page 177- DO NOT need to know) Some bilateral agreements with countries to ensure quality Several agencies within Japan work together develop guidelines

31. Drug Registration Before 1983, formal partnership was needed with a Japanese country 1983 amendment, foreign drug producers can apply directly to import and sell drugs in Japan Japan (along with Europe) prescribe our drugs

32. Terms See page 181 Cell culture, Seed cell lines, MCB and Cell banks - similar definitions to the US terminology CPAC says biologics should be considered entirely new drugs - must undergo complete preclinical and clinical testing again.

33. Manufacturing Criteria Define origin and characteristics of seed cell line Define method of prep, storage and maintenance of MCB QA issues Stability of cells being used

34. Clinical Studies Japan uses Phase I, II, and III testing Same as ours:  Phase 1: pharmacokinetics in healthy patients  Phase II: small group with disease to look at efficacy and continue looking at safety  Phase III: larger group of patients with disease to look at efficacy

35. Canada Parallels drug approval process of FDA in US Canadian drug approval

36. Why are drugs cheaper in Canada? Canadian drug costs