How to Recognize What You Dont Know About the Regulatory Maze Lessons learned from years of experien

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How to Recognize What You Dont Know About
the Regulatory Maze (Lessons learned from years
of experience working with the FDA)
Kathleen R. Gans-Brangs, PhD Senior Director
Scientific Medical Healthcare
Relations AstraZeneca Pharmaceuticals, LP
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The Regulatory Process What to Watch For,
Some Keys to Success

• FDAs Center for Drugs (CDER) Pet Peeves
• http//www/fda/gov/cder/pike/special/2002d.htm
• Introduction to issues along the drug development
  highway (Global and US)
• CDERs Drug Education Forum (Small Business)
• http//www.fda.gov/cder/meeting/de-forum-2005.htm
• Case study FASLODEX (fulvestrant

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Most difficult aspect of .regulatory work (is)
how to recognize who is trustworthy and who is
not and deal with each accordingly. CDER Pet
Peeves

• Overly aggressive sponsor interactions
• Ask same question
• Bypass layers of management
• Argue legal issue(s), not science
• Submission Quality
• Ignore advice, and not inform FDA that their
  advise ignored
• Sloppy documents

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CDER Pet Peeves (2)

• Unrealistic sponsor expectations
• Seek immediate answers to complex regulatory
  issues at meetings without written explanation
• Gaming the system
• Deviate from agreed protocol design
• The sky is falling!
• Do absolute minimum work

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Say What You Mean!

• Health Authority (HA) Please carefully review
  your study size
• If sponsor conducts the study this way HA may
  find methodology wanting during review
• ADVICE Use Special Protocol Assessment
• HA Sponsor should, We recommend..
• ADVICE To increase the likelihood of approval,
  decrease the need for advisory committee, do the
  recommended work
• HA That is a major review issue
• ADVICE Listen! Ask for more detail in the
  meeting and/or after official HA minutes issue if
  not clear. Ask for revision of official minutes
  if needed.
• (e.g., for labeling, may not want to comment
  until review complete)

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Drug Development and Review Where Does it Begin?
Submit IND
Submit NDA
Pre-Human Research
Phase 1
Phase 2
Phase 3
Phase 4
FDA Review
Pre-IND Meeting
EOP2 Meeting
Pre-NDA Meeting
Advisory Committee Meeting
Labeling Risk Management Meetings
Karen Church, Ancile Pharmaceuticals
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Introduction to Issues Along the Development
Highway (Global and US) (1)

• Pre-human (Non-clinical, Pre-clinical)
• ICH 9 month dog study vs. Preamble in Federal
  Register Notice, FDA can ask for 12 month dog
  study for new chemical entity
• Juvenile animals?
• Formulations- do not assume one will be
  sufficient!
• Pediatric Research Equity Act (PREA) through Oct
  2007 need pediatric formulation, pediatric
  program
• Watch for EU regulation, PDUFA IV, changes to
  FDAMA (FDA Modernization Act) in 2007
• Phase 1 What is the right dose?

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Introduction to Issues Along the Development
Highway (Global and US) (2)

• Phase 2 Its not easy anymore!
• Targeted therapies
• Sample collection appropriate consent forms,
  differences in Europe, US laws
• Do regulators have experience in the area? Is
  there regulatory precedent?
• Phase 3 designs and surprises
• End-of Phase 2 meeting most important!
• Use Special Protocol Assessment, modify in
  writing if change inclusion/exclusion criteria,
  statistics
• Superiority vs. non-inferiority trial design
• CMS give formulary placement for me too, as
  good as drugs, devices?

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Introduction to Issues Along the Development
Highway (Global and US) (3)

• Some cautionary tales- global drug development
• ICU
• Screening, disease prevention
• What nurses can do (vs. doctors)
• Post-marketing commitments anticipate cost,
  time
• Earlier disease follow up 10-25 years!?!
• Pediatric patients follow up until puberty

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Case study FASLODEX (fulvestrant) (1)

• Dec 1996 IND filed Oncology Division (two other
  INDs non-oncology indications)
• Jan 1997 End-of-Phase 2 meeting
• Phase 3 FDA recommended (but did not require)
  different comparators in two pivotal trials
  sponsor used same comparator in both trials
• FDA agreed to time to progression as primary
  endpoint only if superiority demonstrated
• Nov 2000, Oct 2001, Multiple pre-sNDA meetings
  requested, granted (Oncology Division)
• NDA format and content
• Trials did not meet primary endpoint of
  superiority in time to progression

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Case study FASLODEX (fulvestrant) (2)

• 28 Mar 2001- NDA submitted, priority review
  requested (new mechanism of action), not granted
• 28 Jan 2002 PDUFA date
• 14 Jan 2002 - Trademark not recommended
• 25 April 2002 FDA approval as FASLODEX
• Approved on non-inferiority in objective response
  rate
• When initial analysis did not support the time to
  progression superiority objective, FDA determined
  that a comparison of response rates could be the
  primary efficacy analysis supporting marketing
  approval Bross et al., Clinical Cancer Research
  94309. 2003
• Agree to 2 year risk management medication error
  reporting commitment, fulfilled 19 July 2004

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In Conclusion

• Build trust, positive corporate reputation with
  heath authorities
• Follow guidance (written and from meetings) or be
  clear when you do not
• Be aware of regulatory precedent
• avoid as many bumps in the drug development
  highway as possible with sound regulatory advice
• THANK YOU!