Guidance for Industry
Interpreting Sameness of Monoclonal Antibody Products Under the Orphan Drug Regulations
[PDF version of this document]
Draft Guidance
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be
submitted within 60 days of publication in the Federal Register
of the notice announcing the availability of the draft guidance.
Submit comments to Dockets Management Branch (HFA-305), Food and
Drug Administration, 5600 Fishers Lane, rm. 1061, Rockville, MD
20852. All comments should be identified with the docket number
listed in the notice of availability that publishes in the Federal
Register.
For questions on the content of the draft document contact
Marjorie Shapiro, (301) 827-0850.
Additional copies of this draft guidance are available from:
Additional copies of this guidance are available from: Office of
Communication, Training and Manufacturers Assistance (HFM-40),
Center for Biologics Evaluation and Research, 1401 Rockville Pike,
Rockville, MD 20852-1448 or by calling 1-800-835-4709 or
301-827-1800, or from the Internet at
http://www.fda.gov/cber/guidelines.htm.
or
Office of Training and Communications, Division of Communications
Management, Drug Information Branch (HFD-210), Center for Drug
Evaluation and Research, 5600 Fishers Lane, Rockville MD 20852
or by calling 301-827-4573, or from the Internet at
http://www.fda.gov/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
Center for Drugs Evaluation and Research (CDER)
July 1999
TABLE OF CONTENTS
- INTRODUCTION
- BACKGROUND
- SCOPE
- INTERPRETATION OF SAMENESS FOR MONOCLONAL ANTIBODY PRODUCTS
- Structural Features of Antibodies
- Sameness for Naked Monoclonal Antibody Products
- Sameness for Antibody Conjugates, Fusion Proteins, and
Bispecific Antibodies
- CHANGES IN ANTIBODY STRUCTURE THAT DO NOT CONSTITUTE
DIFFERENCES BETWEEN TWO MONOCLONAL ANTIBODY PRODUCTS
WITH THE SAME COMPLEMENTARITY DETERMINING REGIONS
- Framework Regions
- Constant Region
- Antibody Fragments
- REFERENCES
Guidance for Industry
Interpreting Sameness of Monoclonal Antibody Products Under the Orphan Drug Regulations
Draft - Not for Implementation
This guidance document represents the Agency's current thinking on
the interpretation of the Orphan Drug regulations as they pertain
to monoclonal antibodies. It does not create or confer any rights
for or on any person and does not operate to bind FDA or the public.
An alternative approach may be used if such approach satisfies the
requirements of applicable statutes, regulations, or both. |
- INTRODUCTION
The regulations implementing the Orphan Drug Act are codified in
21 CFR Part 316. FDA published the Proposed Rule for these
regulations on January 29, 1991 (56 FR 3338) (Ref. 1) and the Final
Rule on December 29, 1992 (57 FR 62076) (Ref. 2). One of the
incentives for orphan drug development is the exclusive approval
of a product for a period of seven years. During this seven year
period, no approval will be given to a subsequent sponsor's
marketing application for the same drug product for the same
indication unless the subsequent product is shown by the sponsor
to be clinically superior, as defined in 21 CFR 316.3 (b)(3).
In determining whether or not two products would be considered
the same, FDA recognized that different criteria were necessary
for macromolecules versus small molecules [21 CFR 316.3(b)(13)].
Macromolecules include a variety of structures including proteins,
nucleic acids, carbohydrates and closely related, complex, partly
definable drugs such as vaccines or surfactants. The current
definition of sameness for protein drugs [21 CFR 316.3(b)(13)
(ii)(A)] however, does not adequately consider the unique nature
of antibodies. The purpose of the present document is to describe
FDA's current thinking on the criteria by which two monoclonal
antibody products would be considered the same under the Orphan
Drug Act and its implementing regulations.
Table of Contents
- BACKGROUND
21 CFR Part 316.3(b)(13)(ii) defines sameness for a macromolecule
as "..drug that contains the same principal molecular structural
features (but not necessarily all of the same structural features)
and is intended for the same use as a previously approved drug.."
Two protein drugs would be considered the same "..if the only
differences in structure between them were due to post-translational
events or infidelity of translation or transcription or were minor
differences in amino acid sequence .." [21 CFR Part 316.3(b)(13)
(ii)(A)]. For monoclonal antibody products, these definitions
lay the groundwork for the determination of sameness but, because
of the unique series of processes involved in creating an antibody
molecule, additional guidance as to what would be considered the
same under the Orphan Drug regulations is needed.
An antibody molecule is composed of four polypeptide chains, two
identical heavy (H) chains and two identical light (L) chains.
Both heavy and light chains are divided into variable (V) and
constant (C) regions. The VH-VL pairs confer specificity for antigen while the constant region of the heavy chain is responsible
for effector functions such as, but not limited to, complement
fixation and antibody dependent cellular cytotoxicity. The
variable and constant regions were so named because amino acid
sequence data showed that the amino terminal regions of heavy and
light chains from different antibodies had different sequences
while the carboxy terminal region amino acid sequences were the
same within a given isotype (class or subclass). Subsequent
analysis of variable region amino acid sequences defined three
hypervariable regions (also known as complementarity determining
regions or CDRs) each in the VH and VL regions which form the antigen binding site of the molecule (Ref. 3).
Antibody diversity is created by the use of multiple germline
genes encoding variable regions and a variety of somatic events.
The somatic events include recombination of variable gene segments
with diversity (D) and joining (J) gene segments to make a
complete VH region and the recombination of variable and joining
gene segments to make a complete VL region. The recombination
process itself is imprecise, resulting in the loss or addition of
amino acids at the V(D)J junctions. These mechanisms of diversity
occur in the developing B cell prior to antigen exposure. After
antigenic stimulation, the expressed antibody genes in B cells
undergo somatic mutation. Based on the estimated number of
germline gene segments, the random recombination of these
segments, and random VH-VL pairing, up to 1.6 x 107 different antibodies could be produced (Ref. 4). When other processes which
contribute to antibody diversity (such as somatic mutation) are
taken into account, it is thought that upwards of 1 x 1010
different antibodies could be generated (Ref. 5). Because of
the many processes involved in generating antibody diversity,
it is unlikely that independently derived monoclonal antibodies
with the same antigen specificity will have identical amino acid
sequences.
Table of Contents
- SCOPE
For the purpose of this document, a monoclonal antibody is a
clonal product defined as any intact antibody, antibody fragment,
conjugate, fusion protein, or bispecific antibody that contains
a VH-VL pair where the CDRs form the antigen binding site.
Antibody fragments or fusion proteins containing only constant
region domains are not within the purview of this document.
The mechanisms generating antibody diversity are the same for all
antibodies whether they are immortalized as monoclonal antibodies
or purified from serum as polyclonal antibodies. The policy
described in this document, however, will apply only to monoclonal
antibody products.
Diversity of the T cell receptor is also generated by multiple T
cell receptor specific germline genes and somatic events similar
to those described for antibodies. The T cell receptor is
membrane bound in its native functional form. The FDA anticipates
the development of soluble T cell receptor products for
therapeutic use. The interpretation of sameness for monoclonal
antibody products in the present document will apply to soluble T
cell receptor products.
Table of Contents
- INTERPRETATION OF SAMENESS FOR MONOCLONAL ANTIBODY PRODUCTS
- Structural Features of Antibodies
As described in section II above, antibodies have two
functional regions, the variable region, which is
responsible for antigen-specific binding, and the constant
region which carries out effector functions. The variable
region is divided into complementarity determining regions
(CDR1, CDR2 and CDR3) and framework regions (FR1, FR2, and
FR3). CDRs 1, 2, and 3 are delineated by amino acid
positions 31-35, 50-65, and 95-102 for heavy chains and
amino acid positions 24-34, 50-56, and 89-97 for light
chains. While these amino acid positions define the
boundaries of each CDR, the lengths of the CDRs can vary
(Ref. 6). The CDRs create the antigen binding pocket of
the molecule through the interaction between heavy and
light chain variable regions while the framework regions
provide the scaffolding on which the antigen binding pocket
sits. The constant region is responsible for antibody
effector functions but, has little influence on antibody
specificity or affinity.
- Sameness for Naked Monoclonal Antibody Products
The definition of sameness for a macromolecule is based on
its principal molecular structure. For the purpose of
determining sameness of naked monoclonal antibodies under
the Orphan Drug Act and its implementing regulations, the
complementarity determining regions of the heavy and light
chain variable regions will be viewed by the FDA as the
principal molecular structural feature of a monoclonal
antibody product. The residues comprising the CDRs will be
those stated in Section A. above as defined by Kabat et al.
(Ref. 6).
The proposed interpretation of sameness for two monoclonal
antibodies is that two monoclonal antibody drugs would be
considered the same if the amino acid sequences of the
complementarity determining regions were the same or if
there were only minor amino acid differences between them.
Other potentially important amino acid differences outside
the complementarity determining regions, or differences due
to glycosylation patterns or post translational
modifications would not per se cause the products to be
considered different unless the subsequent drug was shown to
be clinically superior.
In the Orphan Drug Regulations Final Rule (57 FR 62076),
Section II.B. (Summary of and Response to Comments; Sameness
Versus Difference), comment 31 refers to a suggestion that
a guidance document be developed to describe the differences
in amino acid sequence of a protein which would be considered
"minor". Now, as then, the FDA declines to provide examples
for hypothetical situations. This determination would be
made on a case-by-case basis. The types of information that
would be useful in making such a determination include (but
are not limited to) the sequence of the heavy and light chain
variable regions of the product, any modifications made during
the development process, and whether any particular residues
have been established to be important for antigen binding.
- Sameness for Antibody Conjugates, Fusion Proteins, and
Bispecific Antibodies
Monoclonal antibody products can be conjugated by chemical
methods with radionuclides, drugs, macromolecules, or other
agents or can be made as fusion proteins. A monoclonal
antibody fusion protein contains a VH-VL pair where one of these chains (usually VH) and another protein are synthesized
as a single polypeptide chain. These types of products differ
from naked monoclonal antibodies in that they generally have
an important additional functional element; the active moiety
of a small molecule or the principal molecular structural
feature of the conjugated or fused macromolecule.
The determination of sameness of monoclonal antibodies which
have had relevant functional elements added will be based on
a determination of sameness for the monoclonal antibody
element and on a determination of sameness for the added
relevant functional element (see, for example, 21 CFR 316.3(b)
(13)(i) regarding small molecules and 21 CFR 316.3(b)(13)
(ii) regarding macromolecules. A difference in any one of
these elements may result in a determination that the
molecules are different. Conversely, two monoclonal antibody
conjugates or fusion proteins would be determined to be the
same if both the CDR sequences of the antibody and the
functional element of the conjugated molecule were the same.
Bispecific antibodies are generated by combining a heavy-light
chain pair from a monoclonal antibody of one specificity with
a heavy-light chain pair from a monoclonal antibody of a
different specificity and therefore, have two different sets
of CDRs. Two bispecific antibodies will be considered the
same if both sets of CDRs are the same.
Table of Contents
- CHANGES IN ANTIBODY STRUCTURE THAT DO NOT CONSTITUTE
DIFFERENCES BETWEEN TWO MONOCLONAL ANTIBODY PRODUCTS
WITH THE SAME COMPLEMENTARITY DETERMINING REGIONS
Listed below are potential changes in areas outside the CDRs in
monoclonal antibody products. For the purpose determining sameness
of monoclonal antibodies under the Orphan Drug Act and its
implementing regulations, such changes do not constitute
differences between two monoclonal antibody products with the
same CDRs unless the subsequent product is shown to be clinically
superior.
- Framework Regions
Framework region changes include, but are not limited to,
humanizing a non-human derived monoclonal antibody or
engineering certain framework residues that are important
for antigen contact or for stabilizing the binding site.
- Constant Region
Constant region differences include, but are not limited to,
changing the class or subclass of the constant region,
changing specific amino acid residues which might alter an
effector function such as Fc receptor binding, or changing
the species from which the constant region is derived.
- Antibody Fragments
Intact monoclonal antibodies and antibody fragments with the
same CDR sequences will not be considered different. This
is consistent with FDA's policy regarding peptides and
whole proteins as explained in Orphan Drug Regulations Final
Rule (57 FR 62076), Section II. Summary of and Response to
Comments, B. Sameness Versus Difference, comment 21 where
it is stated that "..in order for a peptide that resembles
a portion of a protein product to be considered a different
drug, FDA will require a clear demonstration that the peptide
is clinically superior to the entire protein."
Table of Contents
- REFERENCES
- Federal Register, 56 FR 3338 1/29/91, Orphan Drug Act:
Proposed Rule, [Docket No. 85N-0483].
- Federal Register, 57 FR 62076 12/29/92, Orphan Drug Act:
Final Rule.
- Kabat, E. A., "The Structural Basis of Antibody
Complementarity". Advances in Protein Chemistry. Vol.32;
pp. 1-75. 1978.
- Max, E. E. Immunoglobulins: Molecular Genetics. In
Fundamental Immunology. Third Edition ( Ed. W. E. Paul)
pp. 315-382, Raven Press, New York, New York, USA. 1993.
- Burrows, P.D., Schroeder, H.W., and M. D. Cooper. B-Cell
Differentiation in Humans. In Immunoglobulin Genes. Second
Edition. (Ed. Honjo, T. and F. W. Alt) pp. 3-32, Academic
Press, San Diego, California, USA. 1995.
- Sequences of Proteins of Immunological Interest. Kabat, E. A.,
T. T. Wu, H. M. Perry, K. S. Gottesman and C. Foeller (Eds.)
U. S. Department of Health and Human Services, National
Institute of Health, Bethesda, MD. 1991.
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