CMC, Preclinical and Clinical Considerations for

CMC, Preclinical and
Clinical Considerations
for Biosimilars and
Follow-on Biologics
By Raymond A. Huml, MS, DVM, RAC; Peter Hicks, PhD;
Kamali Chance, MPH, PhD, RAC; Kevin Howe, PhD; and Ross M. Tonkens, MD, FACP
A
s noted in the article “Follow-on Biologics
in the EU and US,” on page 8 of this issue,
biologics are created from living organisms, either naturally or via genetic manipulation
(e.g., monoclonal antibodies), or are manufactured
from complex building blocks of living organisms
(e.g., siRNA, aptamers, etc.). In either case, they
demonstrate considerable molecular complexity
and heterogeneity, and are more difficult to
characterize physicochemically than synthetic
chemical entities. These differences are reflected
in the regulatory agencies’ refusal to adopt the
same paradigm for generic biologic drugs as for
traditional small molecule products.
This article summarizes some of the issues
pertaining to biosimilars in Europe that are also
likely to impact eventual FOB approval testing
in the US. It focuses on the key parts of the
development package for an FOB marketing
application, including the comparability protocol
exercise and regulatory authorities’ preclinical
and clinical expectations.
CMC Concerns for Biosimilars/FOBs
As for all other drug products, a biosimilar
submission to the regulatory authorities requires
a complete CMC package, which is provided as
Module 3 in the Common Technical Document
(CTD). This CTD section provides complete
information on the development, manufacture
and control of both the active drug substance
and the drug product. EMEA’s Guideline on Similar
Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Quality
Issues is a good starting point. In addition—and
fundamental to defining the overall development
package—is the CMC comparability exercise,
reported as a separate section of the filing. The
manufacturer must carefully design the comparability exercise based upon full knowledge of
the molecular structure and its relevance to the
mode of action. The result is a series of physicochemical tests, alone or in combination with such
biological tests as in vitro or in vivo bioassays, and
receptor binding studies. These tests are applied to
the biosimilar and the selected reference product to
demonstrate similarities and differences between
the two products. Where such testing cannot
establish similarity, or where differences arise, the
outstanding issues must be addressed through supporting preclinical and or clinical work. Biosimilar
comparability testing builds upon earlier guidance
on comparability of recombinant products arising
from manufacturing changes.
Changes introduced early in a biosimilar’s
development will give rise to some predictable
differences from the reference product, assuming
sufficient information on the reference product
is in the public domain and the mechanism of
action—at the molecular level—is well-established. These differences should be assessed as
part of the comparability review and appropriate
testing must be performed. An example would be
change of the host cell line and vector. This is a
common change that can have far-ranging consequences, such as host cell protein and DNA (type
and level) differences requiring that the levels
present be justified and qualified. Cell line change
may also go from internal protein storage requiring cell disruption to a protein expressed directly
into the media, which may impact the overall
product profile with regard to related materials
and impurities. Another difference that may arise
from changing the cell line is an alteration in the
degree and type of glycosylation with potential
changes to product half-life and receptor affinity
and important changes to immunogenicity. These
points and their resulting impacts illustrate why
tight coordination among the three disciplines of
quality, safety and efficacy is paramount before
instituting a biotechnology-derived medicinal
development program.
An important consideration for any comparability exercise is the lack of access to the
reference product drug substance. In a best-case
scenario, the formulation adopted for the reference product may allow direct comparison and be
amenable to the battery of tests to be employed.
However, coformulants may potentially render
some testing inapplicable or interfere with other
procedures, thereby requiring extraction of the
drug substance. Extraction, itself, requires careful
assessment, as it may induce changes that render
the results inapplicable to the product. Before a
definitive comparability testing protocol can be
designed, preliminary studies may be required to
determine test method applicability and whether
the drug product or extracted drug substance will
be used. A corollary to the formulation impact is
the ability to assay the reference product since
certificates of analysis frequently are not available
or the reference product is partially through its
shelf life. Using a nominal value may have marked
effects on demonstrating equivalence in comparator trials or preclinical programs where the
product has a wide specification. Thus, materials
should be assayed for potency prior to use.
Intrinsic to establishing similarity is the complexity of the molecule under investigation.
Proteins (the current focus of biosimilars
RA focus 21
Table 1: Acronyms
CD
Circular Dichroism
CE
Capillary Electrophoresis
CHMP
Committee for Medicinal Products for Human Use
CMC
Chemistry, Manufacturing and Controls
CTD
Common Technical Document
DNA
Deoxyribonucleic Acid
EMEA
European Medicines Agency
FOB
Follow-on Biologic
IEF
Isolectric Focusing
LCMS
Liquid Chromatography/Mass Spectrometry
NCE
New Chemical Entity
NMR
Nuclear Magnetic Resonance
PAGE
Polyacrylamide Gel Electrophoresis
PD
Pharmacodynamic
PK
Pharmacokinetic
siRNA
small (or short) interfering Ribonucleic Acid
TK
Toxicokinetic
UV
Ultraviolet Spectroscopy
and FOBs) can range from polypeptides to
multi-domain proteins with or without posttranslational changes, even ignoring degrees of
heterogeneity. The EU guidance recognizes the
characterization difficulties and issues of variability with the expectation that the biosimilar
approach be applied to highly purified product
that can be thoroughly characterized—essentially
a biotechnology-derived medicinal product. EU
authorities also require full confirmatory clinical
data for follow-on products derived from blood
or plasma, and the case-by-case consideration of
immunologic modulators.
Current emphasis remains on licensing similar first-generation proteins coming off patent.
Similar guidance and comparability concepts will
need to be extended to chemically modified
proteins (e.g., pegylated) as their patents expire.
With these products, subtle differences between
proteins may also affect actual amino acid coupling site(s) (and potential resistance to cleavage)
that may markedly affect the mean residence
time and pharmacodynamic profiles of these
22 January 2008
agents. Nevertheless, while chemically modified
proteins will add yet another layer of complexity
to comparability exercises, the underlying guidance principles will remain applicable.
Characterization of proteins as either drug
substances or drug products utilizes combinations
of techniques. Testing is conducted to establish
the primary and higher-order structures present, the presence of related materials (amino
acid variants, dimers, etc.) and contaminants
arising from the cell line and processing (host
cell proteins, plasmid DNA, peptidase inhibitors,
etc.), as well as the protein’s physicochemical
parameters (molecular weight, isoelectic point,
degree and type of glycosylation, etc). Techniques
employed include, but are not limited to, primary
amino acid analysis, peptide mapping, LCMS (and
its variants), CE, CD, NMR, UV, IEF and PAGE
(normal and denaturing). In many cases, however,
there is no direct link between the data generated and the protein’s overall conformation and
pharmacodynamic effect. Therefore, an in vitro
or in vivo biological assay relevant to the mode
of action is required, which may also necessitate
supplementary receptor binding studies. The
testing program must be able to demonstrate both
differences and similarities. Data produced by the
comparability exercise must be reviewed and put
into context. By the very nature of the material
in question and the processes used to produce it,
differences may arise. Such differences themselves
are not the issue; the ultimate pharmacodynamic
impact and overall safety they may confer must
be assessed. The answer to this can lie outside
the CMC domain. For some, answers are obtained
from biological testing, but for others, the answers
are found in the preclinical and clinical arenas.
CMC comparability is essential to any biosimilar and is absolutely fundamental in defining
the overall development program. However, it
must be recognized that a detailed, comprehensive program necessary to support a regulatory
application will be expensive not only in terms
of money, but also in terms of key personnel and
resources (a major consideration for smaller organizations). For platform-based companies looking
at numerous biosimilars, the overall costs are
multiplied and will be significant—often beyond
the means of all but the most robustly capitalized.
Once a detailed comparability program has been
established, based in part upon preliminary CMC
data, regulatory scrutiny should be sought via
the EMEA Scientific Advice program. Companies seeking advice will not only validate their
approaches, but will benefit from the regulators’
current thinking on any one product as well.
Smaller companies looking to out-license will
particularly enhance their negotiating leverage by
following this proactive approach.
Efficacy Comparisons, Preclinical
Safety, Pharmacokinetics and Clinical
Studies for FOBs
Current guidelines adopted in the EU are likely to
form the backbone of future FDA‑specific guidance
regarding FOBs. EMEA’s Guideline on the Nonclinical and Clinical Issues to be Considered for the
Development of Similar Biological Medicinal Products
(EMEA/CHMP/BMWP/42832/2005) details EU
issues and expectations regarding efficacy, safety
and clinical testing, but these could ultimately
differ in the US. The requirements depend upon
existing knowledge of the reference biological
medicinal product and the claimed therapeutic
indication(s) in addition to reference drug availability and confirmation of that agent’s identity.
Available product- and/or disease-specific
guidelines should be followed, acknowledging
that the FOB manufacturing process will be
optimized throughout development. It is highly
recommended that clinical data required for
the comparability study be generated in parallel with final manufacturing process design to
represent the FOB quality profile expected of the
commercial batches. The clinical comparability
exercise is a stepwise procedure that begins with
pharmacokinetic (PK) and pharmacodynamic (PD)
studies, followed by clinical efficacy and safety
trial(s) or, in certain cases, PK/PD studies only for
demonstrating clinical comparability.
For preclinical and in vitro comparability
testing, assays like receptor-binding studies or
other cell-based assays may be available from
quality-related bioassays. Preclinical and in vitro
comparability testing should be conducted to determine comparability in reactivity and likely causative
factor(s), if comparability cannot be established.
Animal studies should be designed to maximize
information and to compare both reference and
FOB intended for clinical trial use. Animal studies
should therefore be performed in species that are
relevant to humans and should employ state-ofthe-art technology, ideally monitoring a number of
clinically relevant pharmacodynamic endpoints.
For toxicology studies, non-human primates
are likely to be the most relevant species for a
human protein, but occasionally no species may
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RA focus 23
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be relevant. Therefore, direct reference to the
original dossier’s study designs is required for
consideration of species selection. At least one
repeat-dose toxicity study containing toxicokinetic (TK) measurements is expected. These TK
measurements should include determination of
antibody titers and neutralizing capacity. These
latter factors are most relevant in the required
clinical trial and should be built into the clinical
protocol including isotype characterisation.
Toxicity study duration should be sufficient
to enable detection of relevant differences in
toxicity and/or immune responses between the
FOB and the reference medicinal product. If
there are specific safety concerns, these might
be addressed by including relevant observations
(i.e., local tolerance) in the same repeat-dose
toxicity study. Other standard NCE-based
toxicological studies, such as ICH S7 safety
pharmacology, reproductive toxicology, mutagenicity and carcinogenicity studies are not
usually required for FOBs unless indicated by
repeat-dose study results, with reference to the
original product submission.
Generally, one comparative clinical trial is
required to demonstrate clinical comparability. In
certain cases, however, comparative PK/PD studies between the FOB and the reference medicinal
product may be sufficient to demonstrate clinical
comparability. Clinical comparability margins
should be prespecified and justified based upon
clinical grounds. As for all clinical comparability
trial designs, assay sensitivity should be demonstrable and reproducible. If a clinical comparability
trial design is not feasible, other designs should be
explored and their use discussed with the relevant
regulatory authorities.
Overall, and based upon current experience
in the EU, safety data derived from the comparator clinical trial—focusing on immune response
endpoints—are required. However, since the
comparator trial may not generate sufficient data
on long-term safety, the sponsor is expected to conduct postmarketing (phase 4) studies to adequately
address long-term safety. Ongoing monitoring of
FOB clinical safety, including a risk-benefit assessment, must be conducted in the postapproval
phase. The sponsor must provide a risk specification in the application dossier for the medicinal
product under review in the EU. This should
include a description of possible safety issues
related to tolerability of the medicinal product
that may result from a manufacturing process, as
contrasted with the originator, comparator medicinal product. Ultimately, during the authorization
process, the applicant is expected to present a risk
management program/pharmacovigilance plan in
accordance with current guidelines.
In conclusion, the issues outlined in this
article that pertain to biosimilar testing currently
required in Europe are also likely to influence the
eventual FOB approval testing requirements in
the US, once legislation is passed.
Summary
26 January 2008
•CMC comparability remains the
cornerstone of establishing an overall development package for
biosimilars.
•Direct chemical comparison remains essential. In any
comparability exercise individuals
experienced in proving quality are
as essential as those proving safety
and efficacy.
•Only with time, further advances
in analytical techniques and better
REFERENCES
1.The Pink Sheet. “Follow-on biologics deal gives brands 12 years
of exclusivity.” Vol 19, Issue 121, Number 008; 22 June 2007.
2.110th Congress; Bill for Biosimilars (http://help.senate.gov/
Hearings/2007_06_27_E/Biologics.pdf) Accessed 26 July 2007.
For additional information, see references and tables in “Follow-on
Biologics in the EU and US,” on page 8 of this issue
AUTHORS
Raymond A. Huml, MS, DVM, RAC, is Executive Director of Global
Due Diligence for NovaQuest, the product partnering group of Quintiles Transnational Corp. He has worked in various roles for Quintiles
since 1993 and currently serves as a project leader for global due
diligence activities. Huml can be reached at
raymond.huml@novaquest.com.
Peter Hicks, Btech, PhD, is Executive Director of Global Due Dili-
gence for NovaQuest. Following a post-doctoral fellowship with
Boehringer Ingelheim, he was a lecturer in pharmacology at the
University of Manchester. Hicks has 30 years of pharmaceutical
and CRO industry experience and can be reached at
peter.hicks@novaquest.com.
Kamali Chance, MPH, PhD, RAC, is Director of Global Regulatory
Affairs and Medical Writing at Quintiles, Inc. She has more than
20 years of management experience in the healthcare industry
and over nine years of regulatory experience in the pharmaceutical/biotechnology industry. Chance can be reached at
kamali.chance@quintiles.com.
Kevin Howe, BPharm, PhD, CChem, MRSC, CBiol, MIBiol,
MRPharmS, MIoD, Qualified Person, is owner of Epi-Cure Consulting Ltd, a specialist drug development and regulatory organization. He
has over 20 years of varied postgraduate experience in academia, the
National Health Service, pharmaceutical industry and Quintiles where
he was he was Head of The Pharma Consulting Group in Europe. Howe
can be reached at kevin.howe@epi-cure.com.
Ross Tonkens, MD, is chief medical officer of Regado Biosciences, a
company pioneering in discovery and development of antidote-controlled therapeutics directed against specific molecular targets. He
practiced invasive and noninvasive cardiology for more than 20 years
in Beverly Hills, and then Las Vegas, also teaching at UCLA and University of Nevada Schools Medicine and participated as principal
investigator in over three dozen clinical trials. Formerly, Tonkens was
Global Head of Cardiovascular Therapeutics for Quintiles. He can be
reached at RTonkens@RegadoBiosciences.com.
Acknowledgement
The authors would like to thank Dr. Judith Beach, PhD, Esq., Vice
President and Senior Associate General Counsel and Regulatory and
Government Affairs Chief Privacy Officer for Quintiles Transnational
Corp., for her editorial assistance with this manuscript.
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R
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to gis
da te
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understanding of relationships between molecular structure and
function will the development of
FOBs become more focused.
•With improved scientific insight, our
development of biosimilars may
reach a position analogous to that of
generic synthetic chemical entities.
•It is imperative that companies contemplating FOBs consult with
respective regulatory authorities early in the process to obtain buy-in for
the strategic development plan.
RA focus 27