Regulatory Issues US and Abroad

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Regulatory IssuesUS and Abroad

• BIT 230
• Chapters 9-11 Huxsoll

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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

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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

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FDA

• SAFETY and efficacy

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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

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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 sponsors application for approval to
  the FDA

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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)

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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

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Regulatory functions

• Submissions
• Compliance
• Enforcement
• Miscellaneous

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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

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Submission contd

• 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

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Submission contd

• Remember three areas
• premarketing (IND)
• marketing (NDA)
• postmarketing (after on the market)

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Compliance

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

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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

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Compliance

• 3 key points
• documentation
• documentation
• documentation

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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.

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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

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European Regulatory Issues

• Chapter 10

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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)

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Other Products

• Conventional products - submit filing to country
  of choice
• Once approved there, other members of the EU will
  recognize the drugs registration
• Send to central agency only if concerns about
  original registration in Europe

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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

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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

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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)

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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

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Approvals contd

• EMEA doesnt have priority review like FDA does
  may try and implement such a review
• See and review handout from Tufts about EU/EMEA
  summary

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Regulatory Issues in Japan

• Chapter 11

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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!)

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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)

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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

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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

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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

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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.

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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

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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

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Canada

• Parallels drug approval process of FDA in US
• Canadian drug approval

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Why are drugs cheaper in Canada?

• Canadian drug costs