Regulatory Issues US and Abroad

1. Regulatory IssuesUS 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 • documentation • 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