PUBLIC SCIENCE POLICY
Follow-On Biologics: The Evolving
Regulatory Landscape
by Gary C. Messplay, J.D. and Colleen Heisey, J.D.
IMAGE COURTESY OF STOCKXCHNG.COM
Waxman in the 1980s
again for biopharma.
42
T
hroughout the world,
the pharmaceutical
regulatory review and
approval processes in
the United States are
well known and venerated. But is the
country lagging in its development of
a mechanism for approving generic
biological products? Or, is the United
States appropriately moving with
caution out of deference to the compli-
cated legal and scientific issues raised
by follow-on biologics?
The European commission, acting
on a recommendation by the European
Medicines Agency (EMEA) Advisory
Committee on Medicinal Products for
Human Use (CHMP) recently granted
its first marketing authorization for a
follow-on biologic. Sandoz’s generic
The pharmaceutical human growth hormone Omnitrope
was approved in mid-April and repre-
industry questions sents the first biosimilar product to be
marketed in the European Unin (EU).
answered by Hatch- Omnitrope is a follow-on version
of Pfizer’s Genotropin (somatropin
recombinant). The CHMP has also
recommended that regulators approve
have arisen all over generic forms of two recombinant
growth hormones, paving the way
for the first European approvals of
biosimilar biological products. The
Why is the United two products—Sandoz’s generic human
growth hormone Omnitrope, a version
States behind the of Pfizer’s Genotropin (somatropin
recombinant), and BioPartner’s generic
rest of the world in growth hormone Valtropin, which
is BioPartner’s follow-on version of
approving generic Lilly’s Humatrope (somatropin [rDNA
origin] for injection)—represent the
biopharmaceuticals? first application of the European
BioExecutive International MAY 2006
Union’s new approval process for
“biosimilar” products. In addition,
other countries have already approved
generic biological products and those
products have entered their local mar-
kets. Sandoz’s Omnitrope in Australia
was authorized by the Therapeutic
Goods Administration in September
of 2004 for treatment of growth dis-
orders in children, and launched in
November 2005. PLIVA’s erythropoietin
(EPO) biogeneric was approved by
the Croatian Agency for Medicinal
Products and Medical Devices in
June 2005. PLIVA’s product is a generic
version of Janssen-Cilag’s Eprex
(epoetin-alfa), primarily indicated for
the stimulation of red blood cell pro-
duction in patients undergoing dialysis
therapy for chronic renal failure and
patients undergoing chemotherapy
treatment. In anticipation of further
marketing authorizations, PLIVA
has entered business deals with Barr
Laboratories and Mayne Pharma of
Australia to facilitate pursuit of EU
and U.S. approval.
Meanwhile, in the United States,
the potential for any such follow-on
biologic approval is at a standstill.
The products contemplated by Sandoz,
BioPartner, and PLIVA face a novel
situation for a therapeutic product in
the United States: no viable approval
pathway accepted by the U.S. Food
and Drug Administration (FDA). The
FDA names two fundamental barriers
to an approval pathway in the United
States. First, does the FDA currently
have the statutory authority to approve
follow-on biological products? Second,
even if it does have such authority, has science advanced
sufficiently to determine whether a follow-on biologic is
substantially equivalent to an innovator’s product? Until
those legal and scientific issues are resolved, follow-on
biologic products will not be a reality in the United States.
AMERICAN HISTORY
The generic pharmaceutical industry faced a similar issue
some twenty years ago. In the 1980s, there were intense
policy and legislative debates regarding generic drugs.
The debates focused on the need to balance accessibility to
affordable drugs while maintaining a system that rewarded
innovation and provided a means for drug companies to
invest in more research and development of novel thera-
peutic products. Creating a legal and regulatory system to
accommodate that balance was an enormous political and
legal challenge. The outcome was enactment of the Drug
Price Competition and Patent Term Restoration Act of 1984
(referred to as the “Hatch-Waxman” Act), which amended
the Federal Food, Drug, and Cosmetic Act (FDCA) to
address the patent and regulatory approval process for
generic drugs.
Under the Hatch-Waxman Act, Congress set out to
establish a reasonable system by which to speed generic
versions of off-patent pharmaceuticals to market.
Specifically, the Act created a mechanism by which a
generic drug could gain regulatory approval without a full
complement of clinical trials demonstrating safety and
efficacy if the generic product could meet a “sameness”
standard when compared against the innovator drug.
The debate hosted in the development of Hatch-Waxman
resurfaced in the context of follow-on biologics. In 2004,
Congressional interest turned to follow-on biologics as the
Senate Judiciary Committee convened meetings on the
topic to “explore some of the key issues concerning the
legality, feasibility and advisability of creating a new, abbre-
viated regulatory pathway at the [FDA] for the review and
approval of off-patent biological products.” Echoing senti-
ments emanating from Hatch-Waxman, federal lawmakers
again suggested that legislation may be necessary to achieve
a fair balance between incentives and interests in the
biopharmaceutical industry.
DRUGS VERSUS BIOLOGICS
A principal issue in the debate over follow-on biologics is
whether potential follow-on manufacturers can adequately
characterize a protein product given currently available
technologies. Innovator companies question whether
chemical characterization of active ingredients can be
adequate to assure “sameness” of the biological activity and
safety. The inquiry emanates from the nature of biological
products and biotechnology products as distinguished from
traditional drug products.
Biologics differ significantly from traditional drugs in
their size, complexity, structure, and method of manu-
facture. Drug products consist of small molecules, on the
order of dozens of atoms synthesized from defined com-
ponents according to a prescribed production method in
an environment of manufacturing processes and controls.
Biological products are much larger than drugs, made up
of millions of atoms, and are manufactured from living
cells through an elaborate process initiated by specifically
programming a cell line to produce a certain protein in a
highly controlled, sterile manufacturing environment.
Biologics consist of a complex mixture of three-dimen-
sional, heterogeneous proteins as well as impurities that
will affect the biological activity, efficacy, and safety of the
product. The multi-dimensional aspect of biologics makes
the inclusion of impurities expected, and a matter the man-
ufacturer must address during the manufacturing process.
The large structure also means that where contamination
occurs, it may be more difficult to detect and nearly impos-
sible to remove adventitious agents. Contamination of
drugs, on the other hand, is more easily avoidable, detect-
able, and often removable.
Immunogenicity is a major topic of debate over follow-
on biologics, in part because of the difficulty in detecting
small immunogenic differences between biologics. Due to
their size and current scientific knowledge, drug products
rarely elicit an immune response. In comparison, biolog-
ics developed from living cells are capable of interacting
with a human body in unforeseeable ways, thereby trig-
gering immune responses. Not surprisingly, the major
players in biologic product development—the Generic
Pharmaceutical Association (GPhA), the Pharmaceutical
Research and Manufacturers of America (PhRMA), and the
Biotechnology Industry Organization (BIO)—differ in their
views on detecting immunogenicity. Respectively, the views
range from suggesting that pre-approval testing of follow-
on biologics should include identification of the product
factors with the greatest risk for immunogenicity to beliefs
that immunogenicity testing should be the same for an
innovator and follow-on product.
COMPETING ACTS
Aggravating the scientific debate over follow-on biologics
is the fact that there are different approval mechanisms in
place for drugs and biological products. Currently, there is no
agreement as to whether a regulatory pathway exists that
would provide for generic approval of a biological product.
FDA has asserted that the FDCA governs the approval
of drugs and most biological products because the term
“drug” is set forth broadly in the Act, defined as “articles
intended for use in the diagnosis, cure, mitigation, treat-
ment, or prevention of disease ...; and articles (other than
food) intended to affect the structure or any function of the
body ... .” However, biological products are defined under
the Public Health Services Act (PHSA), not the FDCA.
Under the PHSA, a “biological product” means “a virus,
therapeutic serum, toxin, antitoxin, vaccine, blood, blood
component or derivative, allergenic product, or analogous
product, ... applicable to the prevention, treatment, or cure
of a disease or condition of human beings.” To market a
biological product, a manufacturer must obtain a license
under the PHSA by demonstrating that the biological prod-
uct is “safe, pure, and potent” and that “the facility in which
the biological product is manufactured, processed, packed,
or held meets standards designed to assure that the biologi-
cal product continues to be safe, pure,
and potent.”
Under the FDCA, a generic drug
manufacturer may submit an abbreviated
new drug application (ANDA) for
approval to market a generic drug
product. The ANDA process is intended
to minimize the costs associated with
duplicative and costly animal and
clinical research on products FDA
has already determined to be safe and
effective. Approval of a generic drug
under FDA regulations is based on a
“sameness” standard under 505(j) of
the FDCA. A generic drug meets the
sameness standard by establishing
several criteria: the drug must contain
the same active ingredient as the
innovator drug; it must have the same
strength, dosage form, and route of
administration; it must have the same
conditions of use; it must be bioequiv-
alent; and it must be manufactured
according to current good manufacturing
practices. No analogous sameness stan-
dard exists explicitly under the PHSA.
A generic drug manufacturer may also
rely on FDA’s determination of safety
and effectiveness of an innovator drug
when seeking approval of a drug that is
different in certain limited respects
from the innovator drug. In such cases,
the generic manufacturer must provide
additional research and data related to
the differences between the innovator
and modified drug in an application
as described under Section 505(b)(2)
of the FDCA. Both an ANDA and a
505(b)(2) application, by definition,
rely on an innovator’s intellectual
property rights in seeking approval
and require the applicant to acknowledge
patents listed with the FDA by the
innovator at the time of approval.
Follow-on biologic proponents often
cite the 505(b)(2) process as an
adequate regulatory mechanism for
approval of a generic biological product.
BIOSIMILARS IN THE EU
In the midst of FDA’s inaction
regarding follow-on biologics, other
governments, notably the European
Union (EU), have moved forward
in developing approval mechanisms
based on their own scientific justifica-
tion. EU has advanced further than
the United States in developing and
implementing an approval pathway
44 BioExecutive International MAY 2006
for follow-on biological products.
Indeed, it appears that such an EU
approval is imminent. Regulatory
and scientific guidance documents
developed by the European Agency for
the Evaluation of Medicinal Products
(EMEA) have helped position the
EU as the first major governmental
body to authorize a biosimilar prod-
uct. In May 2004, the EU established
the procedures for authorizing and
supervising the regulatory approval of
generic biological products. Since that
time, the EMEA has produced sev-
In the European Union,
the quality assessment
for a biosimilar
product must be
a comprehensive
comparison against the
innovator product.
eral guidelines, draft guidelines, and
concept papers regarding the compara-
bility of biosimilar products.
According to European guidelines,
manufacturers of a new therapeutic
protein product may rely on the
marketing authorization of a thera-
peutic protein already on the market.
However, the manufacturer must
substantiate the quality, safety, and
efficacy of the product. These three
elements represent the main sections
of a new drug application necessary for
any therapeutic product authorization
in the EU. Each section of the dossier
must rely on the same innovator
product as the relevant reference.
The quality assessment for a
biosimilar product must be a com-
prehensive comparison against the
innovator product. The application
may be abbreviated in that the spon-
sor may not be required to repeat all
efficacy and safety studies if the physi-
cochemical and in vitro characteristics
of the two products can be evaluated.
The biosimilar product sponsor must
also demonstrate the two products’
chemical comparability. However, the
EMEA guidelines are quick to point
out that there will be some situations
in which satisfactory equivalence
cannot be demonstrated due to the
complexity of the protein’s structure,
the manufacturing process, and the
effect of product differences on quality,
safety, and efficacy. In such situations,
a full complement of clinical and pre-
clinical data are necessary to support a
therapeutic product dossier. Regardless
of the practical outcome for an indi-
vidual product, the reality of the EU
guidelines means there is a potential
for regulatory approval of a biosimilar
therapeutic protein.
FDA UNDER PRESSURE
As noted above, the United States has
been unable to develop a mechanism
for approval of follow-on biologics.
The pressure being placed on the
agency to take action is building, par-
ticularly in light of the international
movement on biosimilar products.
FDA faces pressure to announce a
policy on the “approvability” of generic
biologics from a number of sources.
In early 2006, following the CHMP
recommendations on Valtropin and
Omnitrope, Senator Orrin Hatch
(R-UT) and Representative Henry
Waxman (D-CA) sent a letter to act-
ing FDA Commissioner Andrew von
Eschenbach urging the FDA to issue
guidance documents already drafted
for follow-on insulin and human
growth hormone (HGH) products.
The two Congressmen have consis-
tently encouraged FDA to establish
a regulatory pathway for follow-on
biologics, using their positions to urge
development of a framework that
would allow generic biologics to enter
the marketplace and thereby help curb
increasing healthcare expenditures.
The letter notes the many occasions
FDA officials have assured Congress
that the agency was diligently consid-
ering the issues necessary to develop
a system for approving generic bio-
logical products. Despite the agency’s
reassurance, Congress has not seen
any significant action on the issue. To
promote movement at the agency, the
lawmakers insisted that FDA “clarify”
what data the agency requires from
a manufacturer seeking to market a
generic insulin or HGH product. The
Congressmen suggested that the two
products could be removed from the
currently stalled regulatory framework
for all follow-on biologic products
because they do not raise the same —
scientific and regulatory issues as other,
more complex biological products.
The letter stated that “[t]here is simply
no excuse—scientific, legal, or other-
wise—for FDA to continue to delay the
release of these guidance documents.”
It also appears that Congress
does not intend to wait indefinitely
for the FDA to enunciate a regula-
tory pathway. While speaking at
the annual meeting of the Generic
Pharmaceuticals Association (GPhA),
Rep. Waxman stated that he would
introduce a bipartisan bill in 2006
to establish a regulatory pathway for
generic biologic products to provide
market competition when a biologic’s
patents expire.
In addition, the FDA is currently
embroiled in litigation with Sandoz
over the non-approval of Omnitrope
in the United States, adding pressure to
the agency to take action on follow-on
biologics. Sandoz originally filed, and
the agency accepted for filing, a new
drug application (NDA) for Omnitrope
in July 2003 after considerable dis-
cussions with the agency. The NDA
contained preclinical, clinical, and
comparability data as well as literature
references and reference to FDA’s —
decision regarding Pfizer’s Genotropin.
FDA notified Sandoz of its inability
to reach an approval decision on the
company’s application in August 2004
but did not specify why the application
could not be approved. Facing a lack
of regulatory action, Sandoz filed suit
against FDA in September 2005 in U.S.
District Court in Washington, D.C. In
its lawsuit, Sandoz demanded that the
agency rule on its pending application.
On April 10, 2006, the District
Court granted summary judgment for
Sandoz and ordered FDA to comply
with its statutory obligations to act on
the application. As the Court notes in
its decision, however, this does not
mean that FDA must opt to provide
Sandoz with an opportunity for a hear-
ing on the question of whether the
application is approvable. By statute,
the hearing must be conducted on an
expedited basis.
FDA’s lack of progress on an issue
undertaken years ago and for which  References 
FDA receives numerous inquiries
each year has several groups asking 1 The Law of Biological
why the agency is unable to develop Medicine: Hearing before the
a regulatory pathway for approval Senate Comm. on the Judiciary,
of Sandoz’s Omnitrope and other— 108th Cong. (2004) (Statement of
similarly situated products. Although Sen. Orrin Hatch).
there are significant legal, regulatory
and scientific issues that FDA could 2 21 U.S.C. §321(g)(1).
rely on to either support or reject the
viability of generic biological products, 3 42 U.S.C. §262(i).
FDA has instead elected to remain
silent. The lack of an articulated opin- 4 42 U.S.C. §262(i).
ion on these issues in the face of the
agency’s development of guidelines 5 Letter from Congressman
was reasonable for a period of time. Waxman to Acting FDA
However, its inaction is becoming Commissioner von Eschenbach.
increasingly more difficult to defend February 10, 2006. http://www.
due to the regulatory and legal prog- house.gov/waxman/pdfs/letter_
ress made in the European Union and fda_2.10.06.pdf
other nations.
GATHERING FORCE
In the past several months, a number
of events have placed increased pres-
sure on the FDA to make significant
progress on developing a mechanism
for reviewing and approving follow-on
biologics: the prospect of biosimilar
product authorization by the European
Union has gained momentum; the
FDA has been sued for its inaction on
a biogeneric application; FDA officials
increasingly refer to the imminent
release of guidance documents that
will resolve the situation; and Congress
has threatened to take direct action if
FDA does not act imminently. These
pressures will undoubtedly result in
FDA taking some stance on the bio-
generic issue in the very near future. 
Gary Messplay is a partner in the
Washington, D.C. office of Hunton &
Williams LLP, where he is head of the law
firm’s Food and Drug Practice Group.
Colleen Heisey is an attorney in the
Firm’s Food and Drug Practice Group.
MAY 2006 BioExecutive International 45