Scientific Considerations for the Development of FollowOn Protein Products

1
Scientific Considerations for the Development of
Follow-On Protein Products

• World Federation of Hemophilia
• 24 September, 2007
• Mark Weinstein, Ph.D.
• Office of Blood Research and Review
• CBER, FDA

2

• Policy is under development
• Will not discuss pending legislation but will
  discuss science

3
Overview

• What is a follow-on protein product?
• Comparison to a generic drug
• Scientific challenges

4
What is a Follow-On Protein Product?

• Follow-on protein products (informal term, from
  Janet Woodcock FOPP congressional testimony )
• Proteins and peptides sufficiently similar to
  an approved product to permit the applicant to
  rely on certain existing scientific knowledge
  about the safety and effectiveness of the
  approved protein product.
• Follow-on protein products may be produced
  through biotechnology or derived from natural
  sources.

5
A Follow-On Protein Product is not a Generic
Product

• Generic Drug Approval (FDC (505(j))
• Abbreviated approval mechanism for a duplicate of
  an already approved drug
• Pharmaceutical Equivalence (PE) same active
  ingredients, dosage form, route, strength
• Bioequivalence (BE) same rate extent of
  absorbance availability at site
• If have PE and BE, no need for clinical or
  pre-clinical studies beyond BE
• Therapeutic Equivalence (TE) PE BE

6
Approval of a Follow-On Protein Product

• abbreviated application (FDC Act 505(b)(2))
  relies, to at least some extent, on the Agency's
  conclusions regarding
• safety and effectiveness (or safety, purity, and
  potency) of an approved product
• contains additional data necessary, other than
  the underlying clinical data supporting the
  approved product, to establish that the follow-on
  product is safe and effective
• (Janet Woodcock FOPP congressional testimony)

7
Example of Data Used to Approve a Follow-On
Product (Omnitrope, a Human Growth Hormone,
single chain,191 amino acid, non-glycosylated
protein)

• Physicochemical active ingredient structure
  highly similar to approved product
• New non-clinical pharmacology and toxicology data
  specific to Omnitrope
• PK, PD, and comparative bioavailability data
  highly similar to approved product
• Clinical efficacy and safety data comparing
  Omnitrope to approved product
• FDA conclusions that the approved product is safe
  and effective for the requested indications of
  Omnitrope, and that Omnitrope is highly similar
  to the approved product
• Omnitrope has not been rated as therapeutically
  equivalent (i.e., substitutable) to other
  approved growth hormones

8
Drugs and Biologics

• A drug an article intended for use in the
  diagnosis, cure, mitigation, treatment, and
  prevention of disease. . . and an article
  intended to affect the structure or any function
  of the body.. . (FDC Act)
• A biological product "a virus, therapeutic
  serum, toxin, antitoxin, vaccine, blood, blood
  component or derivative, allergenic product, or
  analogous product " (PHS Act 351)

9
Differences - Chemical Drugs and Biotech. Proteins
10
Structure of Proteins
Challenges in Analysis of Proteins
Statin MW 400 Da
Fab MW 50,000 Da
PDB 2IG2, 1HW8
11
Protein Challenges in Analysis of Proteins
Folding
12
Challenges in Analysis of Proteins Modifications
13
Molecular Weight Heterogeneity of Plasma-Derived
and Recombinant Factor VIII
Jankowski, et al Haemophilia (2007) 13, 30-37
14
Consideration of Additional Studies
15
Follow-On Discussions

• Scientific Considerations Developing Follow-On
  Protein Products
• Stakeholder Meeting September 14-15, 2004
• http//www.fda.gov/cder/meeting/followOn/followOnP
  resentations.htm
• Public Workshop February 14-16, 2005
• http//www.fda.gov/cder/meeting/followOn/followOnP
  resentations2_2005.htm
• NYAS follow-on Biologics Workshop December
  12-14, 2006
• http//www.nyas.org/ebriefreps/main.asp?intEBriefI
  D477

16
Follow-On Discussions

• Janet Woodcock congressional testimony
• Follow on Protein Products
• http//www.fda.gov/ola/2007/protein32607.html
• Nature Reviews Drug Discovery
• The FDAs assessment of follow on protein
  products a historical perspective
• http//www.nature.com/nrd/journal/v6/n6/abs/nrd230
  7.html