Transcript Benefits of Listing a Patent

ACI’s Conference on
Follow-on Biologics
Defining Biosimilars: Proving (or Disproving)
Interchangeability and Biosimilarity
June 21, 2010
Brian J. Malkin
Partner
212-588-0800
[email protected]
©2010
CONFIDENTIAL
Frommer Lawrence & Haug LLP
Methods for Determining Similarity:
Safety, Purity, and Potency
 Biosimilars Act defines “biosimilar” in two parts:
• “[T]he biological product is highly similar to the reference product
notwithstanding minor differences in clinically inactive components”
PHSA § 351(i)(2)(A)
-
• “[T]here are no clinically meaningful differences between the biological
product and the reference product in terms of the safety, purity, and
potency of the product” - PHSA § 351(i)(2)(B).
 Data supporting biosimilarity includes:
• “[A] clinical study or studies (including the assessment of
immunogenicity and pharmacokinetics or pharmacodynamics) that are
sufficient to demonstrate safety, purity, and potency in 1 or more
appropriate conditions of use for which the reference product is licensed
and intended to be used and for which licensure is sought for the
biological product.” - PHSA § 351(k)(2)(A)(i)(I)(cc).
2
©2010
CONFIDENTIAL
Frommer Lawrence & Haug LLP
Methods for Determining Similarity:
Safety, Purity, and Potency (cont’d)
 PHSA regulations define safety, purity, and potency:
• Safety: “[T]he relative freedom from harmful effect to persons affected,
directly or indirectly, by a product when prudently administered, taking
into consideration the character of the product in relation to the
condition of the recipient at the time” - 21 C.F.R. § 600.3(p)
• Purity: “[R]elative freedom from extraneous matter in the finished
product, whether or not harmful to the recipient or deleterious to the
product. Purity includes but is not limited to relative freedom from
residual moisture or other volatile substances and pyrogenic
substances” - 21 C.F.R. § 600.3(r)
• Potency: “[T]he specific ability or capacity of the product, as indicated
by appropriate laboratory tests or by adequately controlled clinical data
obtained through the administration of the product in the manner
intended, to effect a given result” - 21 C.F.R. § 600.3(s).
3
©2010
CONFIDENTIAL
Frommer Lawrence & Haug LLP
Methods for Determining Similarity:
Safety, Purity, and Potency (cont’d)
 Manufacturing changes requiring comparability protocol (pre-approval)

4
•
Increase/decrease batch size affecting equipment size
•
Modification in fermentation parameters (time, temperature, pH,
dissolved oxygen)
•
Adding, deleting, substituting raw materials (e.g., buffer, media)
•
Mode changes (equipment oriented, e.g., tangential flow filtration to
centrifugation)
•
New working cell bank using modified procedure
•
Reprocessing drug substance/product
•
Addition, deletion, or rearrangement of production steps
•
Other facility-related changes established in BLA
See FDA Guidance for Industry: Comparability Protocols – Protein Drug Products and Biological Products
– Chemistry, Manufacturing, and Controls Information (Draft 2003); FDA Guidance for Industry: Q5E
Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process
(2005).
©2010
CONFIDENTIAL
Frommer Lawrence & Haug LLP
Methods for Determining Similarity:
Safety, Purity, and Potency (cont’d)
 Process-specific considerations for comparability protocol
• Complexity of product structure
• Ability to characterize physiochemical, biochemical, immunological,
microbiological, and biological properties
• Ability to detect differences in product characteristics
• Degree of product heterogeneity
• Effect of potential changes in impurities on product safety
• Robustness of product (ability to remain unaffected by process
changes)
• Rigorousness of process controls

5
See FDA Guidance for Industry: Comparability Protocols – Protein Drug Products and Biological Products
– Chemistry, Manufacturing, and Controls Information (Draft 2003); FDA Guidance for Industry: Q5E
Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process
(2005).
©2010
CONFIDENTIAL
Frommer Lawrence & Haug LLP
Methods for Determining Similarity:
Safety
 Head-to-head clinical trials
•
Clinical trials providing direct evidence of safety, e.g., Phase III studies for
Omnitrope® [Note: Omnitrope has “BX” rating.].
 Immunogenicity assays
•
“Low and acceptable level of immunogenicity”, e.g., antibody levels for
Omnitrope®
•
Neutralizing antibodies assays may be necessary
 See Miacalcin® (Salmon calcitonin nasal spray) citizen petition (FDA-2005-P-0367)
[Note: 2 “AB”-rated generics for Miacalcin® nasal spray using chemical synthesis as
with referenced product, one 505(b)(2) NDA (Fortical®) for the recombinant-derived
product; none for Miacalcin® injection.].
 Toxicological studies [Required for 505(b)(2) NDA (Fortical®) but not ANDAs.]
6
•
Comparative carcinogenic potential
•
Comparative reproductive toxicity.
©2010
CONFIDENTIAL
Frommer Lawrence & Haug LLP
Methods for Determining Similarity:
Purity
 Common impurities in peptide products include modifications arising
from oxidation, deamidation, epimerization, or N-1 deletion.
 HPLC analysis may determine an absence of any peptide-related
impurities to a low detection threshold. (Miacalcin®)
 Peptide-related impurities should be comparable (not necessarily
identical) to the reference product. (Miacalcin®)
• See also Pergonal® (follicle-stimulating hormone and luteinizing
hormone from urine of post-menopausal women) where
uncharacterized urinary proteins were treated as impurities rather than
additional components [Note: Generic versions of Pergonal® obtained
“AB” rating.]
 Immunogenicity study may be required if significant impurity levels or
aggregation not found in the reference product. (Miacalcin®)
7
©2010
CONFIDENTIAL
Frommer Lawrence & Haug LLP
Methods for Determining Similarity:
Potency
 One or more measurements of product integrity:
• Quantitative biological assay (“bioassay”)
 A bioassay measures “the activity of the product related to its
specific ability to effect a given result.”
 In vitro organ, tissue, or cell-based culture systems
 In vivo tests in relevant animal models e.g., rat bioassay for
Pergonal® (menotropins) (USP).
• Non-biological analytical assays
 Immunochemical, biochemical, or molecular attributes correlated to
product-specific biological activity.
 See Miacalcin®; see also FDA Guidance: Potency Tests for Cellular
and Gene Therapy Products (Draft 2008).
8
©2010
CONFIDENTIAL
Frommer Lawrence & Haug LLP
Examples of Manufacturing Changes Where
Similarity Was Questioned
 Myozyme® (alglucosidase alfa)
• Genzyme intended to market both a 160L and 2000L scale
enzyme product (α-glucosidase) (GAA)
• But comparability data in GAA knockout mice revealed AUC was
30% lower for 2000L scale product
• Resulted in withdrawal of 2000L scale product from BLA.
(Note: FDA approved the BLA for Genzyme’s Framingham,
Massachusetts facility, but FDA’s approval letter indicated
Genzyme would manufacture its final product at Genzyme’s
Allston, Massachusetts facility.)
9
©2010
CONFIDENTIAL
Frommer Lawrence & Haug LLP
Examples of Manufacturing Changes Where
Similarity Was Questioned (cont’d)
 Raptiva® (efalizumab)
• Genentech developed cell line and process for monoclonal
antibody for psoriasis and transferred to XOMA, which
manufactured clinical grade material and performed clinical trials
for Genentech
• But when XOMA transferred to Genentech for scale-up and
commercial requirements, minor analytical differences in the
product were confirmed with a finding of significant PK profile
differences
• Forced Genetech to perform another clinical trial with a larger
patient subset for safety and efficacy.
(Note: Withdrawn in 2009 for post-approval safety reasons –
rare life-threatening neurological viral disease.)
10
©2010
CONFIDENTIAL
Frommer Lawrence & Haug LLP
Examples of Manufacturing Changes Where
Similarity Was Questioned (cont’d)
 Eprex® (erythropoietin alpha)
• Ortho Biologics (J&J) reformulated its glycoprotein hormone that
controls erythropoiesis (red blood cell production) in Europe following
the mad cow scare to remove human-sourced material (human serum
albumin) and replace it with sorbitol (polysorbate 80)
• Following reformulation, 200+ patients developed pure red cell aplasia
(PRCA) as a result of neutralizing antibodies generated against
erythropoietin, preventing new red blood cell production and requiring
transfusions
• Animal evidence suggests that sorbitol caused certain organic
compounds to leach from the rubber stoppers, increasing erythropoeitin
immunogenicity
• Ortho started using specially-coated stoppers and changed route of
administration from S.C. to I.V., resulting in return to baseline event
profile.
11
©2010
CONFIDENTIAL
Frommer Lawrence & Haug LLP
Applying for Similarity Determinations
 Existing comparability protocol may pave way for biosimilar
pathway.
 FDA has no legal requirement to develop guidance but may develop
with public input.
 FDA unlikely to provide guidance by letter requests as occurred in
late 2009 for ANDA products.
12
©2010
CONFIDENTIAL
Frommer Lawrence & Haug LLP
Applying for Similarity Determinations
(cont’d)
 Biosimilar applicant may request pre-IND or CMC-specific meetings to discuss

13
•
Data required for approval
•
Cell lines and characterization
•
Physiochemical and biological characterization
•
Removal of impurities (misfolded proteins, aggregates, host cell proteins,
nucleic acid)
•
Bioactivity of product-related substances and impurities
•
Facility design
•
Other validation or assay considerations.
See FDA Guidance for Industry: IND Meetings for Human Drugs and Biologics – Chemistry,
Manufacturing, and Controls Information (2001); FDA Guidance for Industry: Formal Meetings Between
the FDA and Sponsors or Applicants (2009).
©2010
CONFIDENTIAL
Frommer Lawrence & Haug LLP
Questions?
14
©2010
CONFIDENTIAL
Frommer Lawrence & Haug LLP