Transcript Biosimilars-SheldonBradshaw

Biosimilars
Where Are We Now? Where Are We Going?
Sheldon Bradshaw
January 24, 2008
Follow-on Biologics
FDA’s Views on Follow-on Biologics

1. An abbreviated pathway already exists for the follow-on
versions of protein products approved under Section 505 of
the Food, Drug & Cosmetic Act. Section 351 of the Public
Health Service Act, however, does not contain a pathway
analogous to Section 505(b)(2) of the Act.

2. The idea of sameness, as that term is used in the generic
drug approval process under Section 505(j) of the FD&C Act
and applied to small molecule drugs, will not usually be
appropriate for more structurally complex molecules of the
type generally licensed as biological products under the PHS
Act. The question should not be whether they are the same,
but whether they are sufficiently similar.
Follow-on Biologics
FDA’s Views on Follow-on Biologics (cont’d)
3. A finding by the FDA that a follow-on protein product is
sufficiently similar that it may be approved as safe and
effective is distinct from a determination that the follow-on
product would be substitutable for the referenced protein
product.
4. There are significant scientific challenges involved in
determining whether a molecule that is not the same as the
approved or licensed product is nevertheless sufficiently
similar enough to that product so that the FDA’s
conclusions about the safety and effectiveness of the
approved or licensed product can be relied on to support
approval of the follow-on product.
Follow-on Biologics
An Abbreviated Pathway Already Exists For Some
Follow-On Biologics

A biological product is defined, in relevant part, under the PHS
Act as “a virus, therapeutic serum, toxin, antitoxin, vaccine,
blood, blood component or derivative, allergenic product, or
analogous product.”

The PHS Act definition does not include all living organisms.
As a result, some natural source protein products have been
regulated as drugs under the FD&C Act.


E.g., insulin, hyaluronidase, human growth hormones
Under the FD&C Act, in addition to the approval pathway
involving the submission of a full new drug application, there
are two abbreviated pathways for subsequent versions of
already approved drug products.

505(j) – product same as the referenced product

505(b)(2) – product similar to the referenced product
Follow-on Biologics
Under the Two Existing Pathways, Follow-On Protein
Products Have Been Approved As Being Similar To,
Not The Same As, The Referenced Protein Product

Compared to many small molecule drug products, proteins are
usually substantially larger, more complex molecules. Due to
the variability and complexity of protein molecules, current
limitations of analytical methods, and the difficulties in
manufacturing a consistent product, it is unlikely that, for most
proteins, a manufacturer of a follow-on product could
demonstrate that its product is the same as the referenced
product.

As a result, Section 505(j), which is predicated on sameness,
is ordinarily not available for protein products. Instead, the
FDA has used the Section 505(b)(2) pathway to approve some
follow-on protein products, including human growth hormones.
Follow-on Biologics
Follow-on Biologics are Not Automatically Substitutable

A finding by the FDA that a follow-on protein product is
sufficiently similar that it may be approved as safe and
effective is distinct from a determination that the follow-on
product would be substitutable for the referenced protein
product.

To establish substitutability, a manufacturer would need to
demonstrate through additional clinical trials that repeated
switches from the follow-on product to the referenced
product would have no negative effect on the safety of the
product as a result of immunogenicity.

Lack of substitutability may mean no significant cost
savings.
Follow-on Biologics
Significant Scientific Limitations In Establishing
Similarity

There are significant scientific challenges involved in
determining whether one protein molecule is sufficiently similar
to another molecule so that the FDA’s conclusions about the
safety and effectiveness of the approved or licensed product
can be relied on to support approval of the follow-on product.

Current technologies, such as peptide mapping, protein
sequencing, and mass spectroscopy, enable manufacturers to
determine, with certainty, the amino acid sequence of a
recombinant protein. That sequence, however, is the most
rudimentary characteristic of a protein.
Follow-on Biologics
Significant Scientific Limitations In Establishing
Similarity (cont’d)

Analysis of the other aspects of a protein’s structure, e.g., the
folding of the protein’s amino acid chain, requires much more
sophisticated technologies.

While the technology exists to demonstrate structural similarity
between relatively simple protein products, the technology is
not yet sufficiently advanced to allow the FDA to compare
whether more complex protein products are sufficiently similar.

As a result, legislation creating an abbreviated pathway under
the PHS Act analogous to the pathway established by Section
505(b)(2) shouldn’t be viewed (without significant advances in
technology) as opening the floodgates to Biosimilars.
Thank you.
Sheldon Bradshaw
202-955-1575
[email protected]