Biologic therapy is one of the great medical achievements of the
last decades. More than 250 of the commercially available products and more than half
of
the oncologic therapies in development are biologic, and some monoclonal antibodies
(mAbs) are included in the WHO Essential Medicines List.
1
Despite the cost of these drugs, 350 million people
worldwide are estimated to use biologic therapies regularly. In Brazil, many of the
evidence-supported indications of mAbs in oncology (eg, trastuzumab in metastatic
breast
cancer) are not provided by the public health system. Nevertheless, the Brazilian
Health
Regulatory Agency (ANVISA) already has an advanced framework to analyze biosimilar
approvals via two possible pathways: the comparative way, in which strong preclinical
and immunogenicity data are scrutinized, and indispensable phase III clinical trials
are
assessed on a case-by-case basis, and the individual development pathway, in which
quality issue and clinical study requirements are lower, but extrapolations are not
allowed.
2
In 2014, 12% of the
medicines bought by the Brazilian Health Ministry were biologic, and this acquisition
corresponded to 61% of the budget for chronic disease drugs. In fact, many of these
biopharmaceuticals were biosimilars produced in public laboratories by product
development partnerships that encourage technology transfer from private
companies.
3
Some of the most widely used biologic medicines in oncology have patents about to
expire,
opening the market to noninnovative versions of these drugs. There are already many
examples of price reductions of biologic drugs after the marketing of biosimilar agents
and even after biosimilar drug investment announcements.
4
Therefore, in many ways, biosimilars are expected to be
decisive in the oncology scenario, enabling and increasing patients’ access to
treatments and contributing to health systems' sustainability. It is estimated
that the global market for these drugs will expand from the current US$1.3 billion
to
US$7.0 billion in 2020.
5
However, even when a drug becomes patent free, many of the related steps in the
biosynthesis of the product (eg, microorganism or cell-line production, high-performance
liquid chromatography reagents, purification process) remain protected by intellectual
property. As a consequence, identical copies cannot be obtained. Biosimilars are
biologic products that are highly similar, but not identical, to the reference
biopharmaceuticals.
6
Although
some controversy exists regarding this topic,
7
this similarity should be established not only in preclinical
analytic and immunogenicity tests but also in clinical trials,
8
taking into account the different end points to assure
similarity and bringing new specific challenges to the scientific community and
regulatory authorities: Are randomized clinical studies always necessary?
7
What is the right clinical efficacy end
point required in a biosimilar study to ensure its reference product equivalence?
Are
the harder end points (progression-free [PFS] and overall survival [OS]) always the
only
acceptable ones? Or are drug activity end points like response rate (complete plus
partial response) or clinical benefit rate (complete response, partial response, and
stable disease) sufficient to demonstrate reasonable equivalence? And how long should
follow-up be in the clinical noninferiority or equivalence trial to certify that the
adverse event profile of the new product is the same?
9
Making this decision process even more difficult, some of these drugs have approvals
for
multiple clinical indications. For example, trastuzumab, the patent for which expired
in
2014 in Europe and will expire in 2019 in the United States, is indicated for metastatic
and initial human epidermal growth factor receptor 2 (HER2) –positive breast
tumors and advanced HER2-positive gastroesophageal adenocarcinomas. Bevacizumab has
been
used in up to six indications in different countries. With robust preclinical data,
is
it reasonable to demand phase III equivalence clinical trials for each one of these
situations? How can an indication be extrapolated and equivalence assured without
a
specific study in that clinical indication? Taking futility issues into account, is
it
ethically acceptable to repeat all these phase III clinical trials?
Consensus is far away, and the unique agreement on this topic is that multiple points
of
view are acceptable. Recently, even without consensus among regulatory authorities,
some
of the most respected regulatory agencies (including ANVISA) extrapolated for the
first
time a mAb indication and approved an anti–tumor necrosis factor infliximab
biosimilar for clinical indications (Crohn’s disease, juvenile rheumatoid
arthritis, and psoriasis) outside those included in biopharmaceutical phase III studies
(rheumatoid arthritis and ankylosing spondylitis).
10
In oncology, this will be a recurrent theme and a scenario of
great divergence. Nevertheless, there are some critical points to emphasize in the
biosimilar analysis that could overcome much of the disparity and shorten the distance
between the obvious access need and scientific excellence.
Solid Nonclinical Similarity Analysis Is Critical
High-technology analytic methods can provide great
assurance regarding the comparability of a biosimilar to its reference product.
High-performance liquid chromatography, spectrometry, and studies on critical
post-translational isoform modifications (eg, glycosylation of specific amino
acid residues) must be followed by complex in vitro immunogenicity
data.
11
Complement
activation assays and antibody-dependent cellular cytotoxicity studies should be
conducted extensively to reproduce the exact biologic properties of the
innovative reference biopharmaceuticals. The more complex the molecule to be
analyzed, the more extensive and robust the nonclinical analytic dossier of the
biosimilar should be.
Safety issues regarding the immunogenicity of these drugs are the subject of
extensive preclinical concern and intense preclinical research. The clinical
phase of the comparability analysis would be shorter for products with
high-quality preclinical data. The extrapolation of an indication should not be
recommended without this fundamental requirement.
Knowledge and Reproducibility of Biopharmaceutical Mechanism of
Action
Many biologic agents act via identical receptors even in
different diseases. The granulocyte colony-stimulating factor (G-CSF)
filgrastim
12
provides
an example of an extrapolation of an indication based in this assumption. The
same G-CSF receptors are activated in recurrent severe neutropenia,
chemotherapy-induced neutropenia, and the mobilization of CD34+
cells in bone marrow donors, although studies have not examined all clinical
scenarios, and safety concerns have emerged regarding the off-target effects of
such drugs, including induced myelodysplastic syndrome and leukemia with
G-CSF
13
and impaired
cancer control with erythropoietin.
14
On this point, extrapolation of indications for mAbs is
a more complex issue, because the mechanisms of action can be diverse (target
inhibition and immune activation) in different patients and diseases. The
independent contributions of complement activation and antibody-dependent
cellular cytotoxicity responses are difficult to quantify for each specific
biopharmaceutical mechanism of action. For long-term responders, these immune
mechanisms are particularly crucial, and the in vivo immunogenicity of these
medicines should be extensively scrutinized to overcome any immune differences
between the biosimilar and its reference product.
15
Different targets or receptor isotypes
involved in the mechanisms of action of a biosimilar in multiple indications
make extrapolation more difficult.
Sensitive Populations As Correct Targets
Although some controversy exists regarding the extent to
which randomized clinical trials are always necessary to address and confirm the
similarity of biopharmaceuticals,
7
in oncologic therapeutic mAbs, because the biologic effects
are usually mild and the drugs indications often involve chemotherapy
combinations, clinical similarity is still a major issue in addressing
similarity. Relevant differences between biosimilars and their reference
products in equivalence or noninferiority trials could be more difficult to
discern in the wrong population. For trastuzumab in breast cancer indications,
the stage II to III breast cancer population is usually a uniform sample to
measure drug activity. Patients can be selected by age and lymph node status but
usually have uniform nutritional status and basic characteristics that would
barely modify the drug clinical activity. In contrast, a metastatic breast
cancer population can be a much more heterogeneous group, because many variables
can interfere with the compound antineoplastic action. The numbers of previous
lines of therapy, different times to recurrence, changes in hormone sensitivity
profiles, and nutritional status are some of the baseline characteristics that
would bias the population sample and hide differences in the results. In this
situation, it is more reasonable to confirm similarity first in the more
sensitive population (in this case, the localized breast cancer indication) and
then extrapolate to other clinical situations. The more sensitive population is
not always an easy choice. The different indications of bevacizumab and
rituximab are examples of how difficult the selection of a more sensitive
population could be.
Use of Surrogate End Points
Hard end points are typical of pivotal registry studies
of innovative drugs. OS and PFS are typical hard end points to be obtained even
in equivalence or noninferiority study designs, when the CIs should be narrow to
rule out any efficacy difference. These long-term end points demand long periods
of study follow-up and convert phase III trials into expensive scientific tools.
Regulatory authorities around the world favor the use of surrogate end points,
such as complete pathologic response in localized breast cancer, in place of the
traditional OS and PFS end points. In many cases, within metastatic disease
studies, drug activity end points such as response rate or clinical benefit rate
are proposed as substitutes for PFS as preferred end points. This was the case
in the trastuzumab biosimilar study results recently published.
16
The objective response rate at
24 weeks was 69.6% with the biosimilar versus 64% with trastuzumab. The lack of
difference in efficacy based on response was within a narrow, predefined
equivalence margin. These assumptions are widely accepted but demand, as said
before, a robust preclinical characterization of the biosimilar and
pharmacologic and immunogenic similarities to the reference product.
15,16
Postmarketing Surveillance and Pharmacovigilance
Another consensus among regulatory authorities for
biosimilar drugs around the world is the requirement of a complete
pharmacovigilance plan of action. This surveillance is critical to report and
compare long-term adverse reactions (eg, cardiotoxicity of anti-HER2
biopharmaceuticals) that are not expected to come up in equivalence or
noninferiority studies, when the drug activity end points (response rates) would
be the primary objective. Like any innovative drug approval, a correct
pharmacovigilance plan should be emphasized to protect the patients and increase
the medical knowledge about any issue regarding adverse events and long-term
safety. This recommendation became stronger after the peginesatide (an epoetin
alfa biosimilar) incident, when the induction of neutralizing antibodies
cross-reacted with endogenous erythropoietin, resulting in more than 200 cases
of pure red-cell aplasia.
17
Postmarketing studies
18
are
crucial to follow these issues, even more so for biosimilar drugs, when the
extrapolation of clinical indications is being considered. Permanent
postregistry reporting of efficacy and safety data would consolidate information
that would otherwise be unavailable at the time of biosimilar approval. Many
regulatory authorities, such as ANVISA, are dealing with this issue via 5-year
renewable approvals on the condition the registry is maintained with adequate
pharmacovigilance reports.
There are many concerns about biosimilar postmarketing data. In many countries,
pharmacovigilance reports are not incorporated into medical practice like they
should be. In Brazil, most oncologic treatment centers are not accustomed to
providing reports and information concerning adverse reactions or efficacy.
After medical school, Brazilian physicians are still not aware of the critical
importance of a proper pharmacovigilance culture. Pharmacovigilance data are
particularly important in indications that have been extrapolated, where
efficacy clinical data are pending.
The development of reliable biosimilars should be a major commitment among all
health providers for oncologic patients. Pharmaceutical companies, regulatory
authorities, the scientific community, and assistant physicians should align
procedures to encourage the production of high-quality biopharmaceuticals as
effective and safe as their reference products. Medical societies should
encourage members to approach the topic and reinforce statements that guide
prescribers
19
through
the complex concepts of biosimilars. There is little disagreement that
biologically similar drug extrapolation of indications will be a necessary step
in improving access to these medicines. Extrapolation should be guided by
high-quality preclinical and clinical data. At this moment, consensus is being
built about how to extrapolate indications without compromising the safety or
efficacy of these agents. Every step on this path should be taken with rigor and
responsibility. The reliability of biosimilars should not be compromised by our
urgent need to provide access to treatments. Quality comes first.