|European Pharmaceutical Contractor
| As biosimilar developers seek regulatory approval for their compounds, clear guidelines on what is required will become more critical in the trial design stage, especially as developers seek approval for more complex monoclonal antibodies representing some of the most lucrative opportunities.
Despite the fact that the biosimilar market is well established in
Europe and estimated to be worth $4 billion globally by 2015, a clear
approval path for many of these products is not known.With regulations
just starting to emerge in both Asia and the US, a challenge for
biosimilar developers and the contract research organisations (CROs)
they employ is to create clinical programmes that will support global
registration, while taking into account the unique requirements of each
regulatory body – some of which have yet to be defined.
In Europe, the biosimilar regulatory pathway includes both an
overarching guidance for biosimilars, and specific guidelines for
recombinant erythropoietin, insulin, growth hormone and G-CSF. In
Japan, the Ministry of Health, Labour and Welfare (MHLW) issued a
guidance document in 2009 regarding follow-on proteins, and Sandoz
gained approval of Somatropin shortly thereafter. In the US, the 2010
Patient Protection and Affordability Act gave the FDA the authority to
approve biosimilars utilising a new regulatory pathway known as 351k,
and the agency held a public meeting in November 2010 to gather input
as it shapes its own biosimilar guidance document.
Japan’s biosimilar guidance has many similarities to European standards
except a few variations, such as the fact that the MHLW does not
typically require data on safety pharmacology or genotoxity but will
assess the data on absorption, distribution, metabolism and excretion.
Experts predict that the principles of biosimilar development in the US
also will be similar to that of Europe – in that they will require a
full quality dossier with a comparability programme and detailed
product characterisation comparison with, optimistically, a reduced
preclinical and clinical programme – but with additional
variations.Hotly debated issues at the FDA’s open meeting included:
The variations and unknowns of biosimilar development make the creation
of a global clinical trial plan challenging. This article will examine
several key considerations and provide a few recommendations.
- How to define similarity between the innovator biologic and the biosimilar product
- In what situations the two products might be interchangeable
- How much data would be required for approval of the biosimilar
- What pathway would allow the biosimilar to gain approval in multiple indications
- Whether or not developers of biosimilars should have the option
to choose between the new 351k pathway and a traditional biologics
All biosimilar trials must compare the biosimilar product to the
innovator biologic. In some cases, the recommended primary efficacy
endpoint for the comparative study is the same as for the original
approval of the innovative biologic,providing a clear development path
that is likely to be applicable on a global basis. For example, the
primary endpoint for biosimilar erythropoietin in chronic renal failure
is a measure of the mean change in haemoglobin, with a coprimary
endpoint of the average weekly dosage per kilogram of body weight
during the last four weeks of treatment. This strategy is laid out in
European guidance documents and has been validated through other
biosimilar clinical trial programmes, such as for Hospira’s Retacrit.
In some cases,however, the primary endpoint utilised for approval of a
biosimilar may differ from that used in the approval of a new biologic
for the same indication. European regulators have emphasised that the
focus of the biosimilarity trial is not to benefit the patient, but to
demonstrate equivalent efficacy and safety compared to the reference
product.The benefit to the patient has already been established by the
In cancer, for example, the preferred primary endpoint to prove
efficacy is often progression-free or disease-free survival, or overall
survival. Such endpoints may not be feasible for establishing
biosimilarity, since they may be influenced by factors not attributable
to differences between the biosimilar and the innovator biologic, such
as tumour burden, previous or subsequent lines of treatments,
underlying clinical conditions and so on.A primary endpoint that
measures disease activity, such as response rate,may be more
appropriate, with survival measured as a secondary endpoint. Such an
approach,however, must be developed through frequent communication and
close contact with each regulatory body, given that cancer endpoints
have been the subject of much debate even before adding biosimilars to
Developers of biosimilars for cancer must also work closely with
regulators if the standard of care for the disease has recently
changed. In such cases, even if the biosimilar trial design and
endpoints could theoretically mirror the Phase 3 programme used by the
innovator product, the therapeutic combination used in that programme
may no longer be attractive to patients and investigators. For example,
the monoclonal antibody Rituxan (rituximab) was approved based on a
Phase 3 trial that combined it with the chemotherapy regimen CVP
(cyclophosphamide, vincristine and prednisone), but recent studies have
shown greater benefit of Rituxan combined with bendamustine.
In some cases,primary endpoints specified in European guidance
documents may not represent the best choice for US trials. In Europe,
biosimilar insulin products are not required to conduct a clinical
efficacy trial if they have done the necessary preclinical work.
Instead, the required clinical study focuses on safety and,
specifically, immunogenicity over at least 12 months, with the
comparative phase lasting at least six months.The primary outcome
measure in such a trial should be the incidence of antibodies to the
test and reference medicinal product, while efficacy endpoints such as
HbA1c, fasting plasma glucose, change in prandial and basal insulin
dose, and other measures would be secondary.
In the US,however, since guidelines have not yet been established, some
biosimilar developers are choosing to conduct efficacy trials using
change in HbA1c as the primary endpoint. Secondary endpoints might
include fasting plasma glucose, change in insulin dose and change in
body weight, as well as safety measures such as adverse events,
injection site reactions,hypoglycaemic events and immunogenicity as
measured by antiinsulin antibodies.
Additional Design Considerations
Statistical considerations may also differ between the US and Europe.
In insulin trials, for example, a sample size based on the European
primary immunogenicity endpoint is not possible due to the lack of
information on the incidence of insulin antibodies on the test and
reference products.The sample size must instead be based on
demonstrating that the biosimilar is noninferior to the reference
product by measuring change in HbA1c, which is often a secondary
endpoint in European insulin biosimilar studies, although it may be a
primary endpoint in the US.The sample size must also be sufficient to
The draft FDA 2008 Guidance for Diabetes Mellitus recommends using a
limit margin of 0.3 to 0.4 per cent for the HbA1c noninferiority
assessment.This guideline is also used in biosimilar trials.
The available European guidance documents often provide detailed
information regarding statistical analyses, and although the FDA has
yet to provide guidance, the agency is expected to provide a similar
level of statistical detail. Statistical standards may shift,however,
with the emergence of the FDA’s official guidance, as experts expect to
see novel approaches to trial design emerge.
The government’s rationale for supporting biosimilars is to provide
lower-cost biologic treatments to patients, but biosimilars will never
achieve the steep price discounts of generic drugs due to the
complexity of their manufacturing. Add to that a regulatory pathway
that requires thousands of patients to establish equivalence, and the
price differential narrows even more. Innovative trial designs that
utilise surrogate endpoints and new statistical methodologies will be
essential as a means to truncate the biosimilar clinical development
path and realising cost savings.
Efficient, yet thorough, clinical pathways will become even more
critical as biosimilar developers begin to seek approvals for complex
monoclonal antibodies, which represent some of the most lucrative
biosimilar opportunities. European regulators have already issued a
draft guidance document for monoclonal antibodies, stating that the
appropriate pathway for each biosimilar antibody will be decided on a
case-by-case basis, but in general supporting the use of surrogate
endpoints to allow smaller trials.
The FDA’s thinking on such matters has yet to be revealed, but last
year’s approval of Momenta Pharmaceuticals and Sandoz’s generic version
of Lovenox (enoxaparin, Sanofi-aventis) was generally viewed as
supportive of the case for truncated clinical pathways.Enoxaparin is a
complex protein-based drug – the most complex the FDA has tackled to
date – and the agency approved it based on only preclinical data and
earlyphase clinical trials. European regulators have yet to approve a
biosimilar for the low-weight molecule heparin, and experts expect that
such an endeavour would require late-phase trials.
Thus, even though the FDA took several years to approve Momenta and
Sandoz’s drug, it was still seen as a win for biosimilars.And of
course, the extended time to reach a decision was still an improvement
over the FDA’s first biosimilar approval back in 2006, when Sandoz had
to sue the agency to gain clearance of Omnitrope. Much regulatory
progress has been made, and as development continues, sponsors and
their CRO partners will be better positioned to greatly expand the
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