Different drug regularity bodies in different countries.
Fda biosimilar guidelines review
1. FOCUS ON... the regs
Looking at the Recent
FDA Biosimilar Guidelines
Immunogenicity Concerns and
Extension to Other Classes of Drugs
by Vera Weinstein
S
mall-molecule treatments are (www.photos.com)
invaluable in providing
symptomatic benefits for an
array of illnesses. However,
many serious conditions — ranging
from cancer to autoimmune disorders
— respond better to more
sophisticated complex drugs such as
therapeutic biologics and nonbiologic
complex drugs (NBCDs). The latter
are medicinal, nonbiological products
in which the active substance is not a
homomolecular structure, but rather
consists of a number of different
(closely related) structures that cannot
be fully characterized. The US Food
and Drug Administration (FDA)
defines a therapeutic biologic as “a
protein derived from living material
(such as cells or tissues) used to treat outlining necessary steps for for biosimilars two years ago, when
or cure disease” (1). submitting biosimilar drug President Barack Obama signed the
Until recently, pharmaceutical applications. The agency’s attention to Patient Protection and Affordable
companies in the United States had detail came about as a result of past Care Act (PPAC Act) into law on 23
no procedure to follow when issues seen with complex therapies March 2010, amending the Public
submitting applications for “generic” such as interferons, which produced Health Service Act (PHS Act) .The
or follow-on versions of biologic drugs immunogenicity issues (neutralizing relevant statutory provisions are also
(now called biosimilars). And still, no antibodies) in multiple sclerosis (MS) referred to as the Biologics Price
clear guidelines are available for patients (2). The guidelines address Competition and Innovation Act
NBCDs. Despite expiring patents on issues often associated with complex (BPCI Act) of 2009 (3). Similar to the
biologics, this was a complicated issue products — such as immunogenicity Hatch–Waxman Act, which defined
because even slight changes in protein concerns — by defining specific safety an approval pathway for small-
structure (such as small differences in and efficacy testing requirements that molecule generics, the BPCI Act was
amino-acid sequence) could cause will be expected with submissions. aimed at a parallel objective for
serious side effects (e.g., immunogenic biosimilars.
reactions) in patients. Pathway to a Biosimilar Guidance In one recently released draft
On 9 February 2012, the FDA The FDA began its process of guidance, the FDA defines biosimilars
released three draft guidelines developing regulatory requirements or biosimilarity as “highly similar to
10 BioProcess International 10(6) J une 2012
2. the reference product, notwithstanding Alliance Urges a Cautious Approach for Patient Safety
minor differences in clinically inactive In response to the US Food and Drug when it comes to the requirement of
components . . . and there are no Administration’s (FDA) draft guidance on clinical studies and pharmacovigilance.
clinically meaningful differences approving biosimilar medicines, the There can be no grey area when it comes
between the biological product and the Alliance for Safe Biologic Medicines to patient safety.
reference product in terms of the (ASBM, www.safebiologics.org) “Unwanted immunogenicity is the
safety, purity, and potency of the submitted comments to the agency in preeminent safety challenge associated
product” (4). The FDA notes the April 2012 outlining recommendations with biological therapeutics and can
importance of ensuring similarity for ensuring that patient safety is at the result in unexpected or sometimes
between a reference product and a forefront of the biosimilars pathway. severe adverse effects. The predictive
ASBM states that effective value of animal studies is often
biosimilar by taking into account the
implementation must incorporate insufficient to characterize
“structure, function, animal toxicity, prudent measures, including
and human pharmacokinetics and immunogenicity in humans. Clinical
• analytical data and clinical studies to studies, in addition to analytical
pharmacodynamics” of the reference
fully characterize biosimilarity and methods, are necessary to weed out
product (4). Additionally, “the nature immunogenicity ineffective and unsafe drugs —
and complexity of the reference innovator biologics and biosimilars —
• traceability measures including unique
product will be considered along with before they are ever a risk to patients.
nonproprietary names for all biologic
the degree of characterization of the therapies, transparent product labels, “In the unfortunate situation that
mechanism of action (MOA) of the and notification to patients and problems arise, measures must be in
reference product, the extent to which physicians for clinical assessment and place to accurately and promptly connect
pharmacokinetic and adverse event reporting. a specific patient to a specific product.
pharmacodynamic tests predict clinical Before designating a biosimilar to be Our current pharmacovigilance system is
outcomes, the extent of clinical “interchangeable” with its reference not equipped to distinguish a biologic
experience and appropriate endpoints product, ASBM says, US regulators must reference product from its biosimilars.
and biomarkers, and the extent of any recognize and address that the similarity Unique nonproprietary names for
clinical experience with the proposed between reference and biolosimilar biosimilar and innovator compounds
product” (4). products may change over time due to ensure we will be able to effectively track
manufacturing or environmental and trace a product to an adverse event.
Similar criteria are seen in the
variations. This must be implemented prior to
European Union’s regulatory pathway biosimilar market entry.
for biosimilars, which was released by The organization outlined clear, concrete,
and achievable ways to manage risk and The Alliance for Safe Biologic Medicines
the European Medicines Agency
thereby prioritize patient safety. Richard (ASBM) is an organization composed of
(EMA) in 2005. In Europe, diverse healthcare groups and
companies submitting applications for Dolinar (ASBM chair) released the
following statement as he submitted the individuals from patients to physicians,
biosimilars must show that their innovative medical biotechnology
coalition’s comments to the docket:
generic products are closely related to companies, and others working together
reference medicines and do not have “We are pleased with the FDA biosimilar
to ensure that patient safety is at the
draft guidance, but it leaves a lot of
any meaningful differences in quality, forefront of biosimilar policy discussions.
questions unanswered — particularly
safety, or efficacy (5).
Additional guidelines are needed
for NBCDs that fall outside the realm of the reference products being generic manufacturers could not
of both small molecules and biologics, reproduced. Such highly complex demonstrate that their products
but the FDA biosimilar guidelines are drugs will require research into the contained the same active ingredient as
an important first step in defining specificities of their make-up — e.g., the reference product. Although
regulatory considerations for ensuring characterizing method of action sodium estrone sulfate and sodium
affordable patient access to safe and (MoA) — and proper testing needed equilin sulfate were thought to be the
effective therapies. to demonstrate similarity to their only active Premarin ingredients,
Because biosimilars are projected to reference products. laboratory and clinical studies
be a multibillion dollar industry, they suggested that other active ingredients
will have implications for the Expanding the Guidelines could not be identified. In the FDA
pharmaceutical industry and patients to Other Complex Drugs statement, Center for Drug Evaluation
overall. Integrating affordable Although they are not biological drugs, and Research (CDER) director Janet
biologics into the market will provide NBCDs can be just as complicated to Woodcock stated, “Based on currently
more patients with access to life- characterize as biologics, warranting available data, there is at this time no
saving drugs, and companies will be the need for their own generic way to assure that synthetic generic
competing to supply them as soon as guidelines (6). For example, in 1997 the forms of Premarin have the same active
possible. Additional data may need to FDA refused to approve generic ingredients as the brand-name drug.
be provided with biosimilar versions of Premarin tablets (an NBCD This is essential for determining they
applications, depending on the nature used for estrogen replacement) because are equivalent to the brand drug, and is
12 BioProcess International 10(6) J une 2012
3. •
3 Implementation of the Biologics Price
also a legal requirement for their Competition and Innovation Act of 2009. US
approval” (7). Food and Drug Administration: Rockville,
Fortunately, a lot of groundwork for MD, 10 March 2011; www.fda.gov/Drugs/
the NBCD guidelines now has been GuidanceComplianceRegulatoryInformation/
All classes of ucm215089.htm.
established by the biosimilar pathway
4 CDER. Guidance for Industry: Scientific
— including the need for a stepwise complex drugs must Considerations for Demonstrating Biosimilarity to
approach to address immunogenicity be held to at a Reference Product. US Food and Drug
issues that can arise with these drugs. Administration: 9 February 2012; www.fda.
NBCDs would also need to be least the same gov/downloads/Drugs/GuidanceCompliance
evaluated case by case to determine strict standards as RegulatoryInformation/Guidances/
UCM291128.pdf.
whether clinical trials are necessary if biosimilars to ensure
5 Guideline on Similar Biological Medicinal
inadvertent chemical and physical that the follow-on Products. European Medicines Agency:
changes (such as aggregation) can London, UK, 30 October 2005; www.emea.
greatly affect their immunogenicity versions are safe for
europa.eu/docs/en_GB/document_library/
profile. Already, a generic version of patient consumption. Scientific_guideline/2009/09/WC500003517.
one NBCD has caused pdf.
immunogenicity effects that were seen 6 Immunogenicity of biosimilar Low
Molecular Weight Heparins. Generics and
only in longer-term clinical trials.
Biosimilars Initiative: Mol, Belgium, 22 April
Copaxone injection is an 2011; www.gabionline.net/Biosimilars/
glatiramoid-class NBCD therapy for changes to biologics and NBCDs can Research/Immunogenicity-of-biosimilar-low-
multiple sclerosis that produces extreme cause for patients. In a 2009 article, molecular-weight-heparins.
immunogenicity effects when altered. It Eva-Maria Jahn of the University of 7 CDER. FDA Statement on Generic
is a safe and efficacious MS drug Duisburg-Essen and Christian Premarin. US Food and Drug Administration:
Rockville, MD, 25 June 2009; www.fda.gov/
produced by Teva Pharmaceuticals as a Schneider of the Max Planck Institute
Drugs/DrugSafety/PostmarketDrugSafety
mixture of polypeptide sequences with noted that “as the consequences of InformationforPatientsandProviders/
immunomodulating activity. Teva such immune reactions to a bio- DrugSafetyInformationforHeathcare
pursued development of a follow-on therapeutic drug may lead to Professionals/PublicHealthAdvisories/
glatiramoid (Protiramer) by introducing potentially serious side effects and/or ucm169045.htm.
slight changes to the Copaxone loss of efficacy, it is essential to adopt 8 Data on File. Teva Neuroscience, Inc.:
Petach Tikva, Israel.
downstream synthesis procedure. an appropriate strategy for the
9 Jahn E, Schneider C. How to
Despite similarity in the basic assessment of immunogenicity that
Systematically Evaluate Immunogenicity of
polypeptide characteristics, and involves assay development, and Therapeutic Proteins: Regulatory
although Teva did not initially detect bridging of results to and from clinical
280–286. •
Considerations. New Biotechnol. 25(5) 2009:
those in short-term preclinical testing, development from early on” (9).
chronic Protiramer treatment in animal Immunogenicity is clearly an
trials over time led to a number of important component for
Vera Weinstein, PhD, is director of
severe side effects: systemic toxicity, consideration, and all complex drug
scientific affairs, CMC Israel, and Europe
extensive fibrosis, organ damage, and applications should be assessed case by GBP R&D at Teva Pharmaceuticals,
eosinophilia. Those results were case. All classes of complex drugs 5 Basel Street, Petach Tikva, 49131 Israel;
drastically different from what was seen must be held to at least the same strict 972-3-9267267, fax 972-3-9234050;
with the original drug, which has over standards as biosimilars to ensure that vera.weinstein@teva.co.il.
one million patient years of success (8). the follow-on versions are safe for
No tests exist that can characterize and patient consumption. By forming
quantitate the active ingredients of regulatory pathways based on a To order reprints of this article, contact
glatiramer (the drug’s generic name). totality-of-the-evidence approach for Rhonda Brown (rhondab@fosterprinting.com)
1-800-382-0808. Download a low-resolution
Because of that — and Teva’s inability highly complex drugs, the FDA and PDF online at www.bioprocessintl.com.
to characterize the product’s MoA — EMA will ensure that patients get
creating a safe and effective follow-on access to the best care possible while
version could prove to be extremely continuing to ensure that safety
difficult. A lack of similarity in remains a top priority.
complex drugs can lead to severe
consequences, evident only when tested References
in long-term nonclinical or adequate 1 Drugs@FDA Glossary of Terms. US Food
and Drug Administration: Rockville, MD, 2
clinical trials.
February 2012; www.fda.gov/Drugs/
informationondrugs/ucm079436.htm.
Safety Cannot Be Compromised 2 Immunogenicity of Therapeutic Biological
The above examples illustrate Products, Volume 112. Brown F, Mire-Sluis
significant consequences that minor AR, Eds. S Karger: Basel, Switzerland, April
2003: 3–11.
14 BioProcess International 10(6) J une 2012