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Think Globally, Act Locally

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:
  • 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 license application
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.

Primary Endpoint

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 reference biologic.

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 the equation.

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 demonstrate safety.

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 biosimilar market.

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Hans-Peter Guler is Senior Vice President of Clinical Development in Endocrinology and Cardiovascular at INC Research. He has more than 20 years of experience in clinical research. Prior to joining INC Research, Hans-Peter served as Chief Medical Officer/VP Clinical Development at Phenomix for six years, after having held positions of increasing responsibility with Regeneron Pharmaceuticals Inc, Chiron Corp and Ciba- Geigy Corp. His work in clinical research included studies at all stages from first-in-man to large registration trials. Prior to accepting his first job in the industry, he conducted some of the early studies with recombinant insulin-like growth factor 1 in academia. He is an author of over 30 peer reviewed articles. Hans-Peter trained in Switzerland and received his MD from the University of Zurich. Email:
Hans-Peter Guler
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