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International Clinical Trials

Like Minded

The first essential and fundamental stage of biosimilar product development is a clear understanding of the specific nature of these therapeutic proteins, as well as the demands relating to proper planning, conduct and documentation in order to facilitate future marketing authorisation.

Scientific guidelines published by the EMA over the last decade describe the concept of biosimilar medicinal products and the entire development process. In Central and Eastern Europe (CEE), these guidelines constitute the principal, comprehensive source of information about biosimilars for manufacturers, CROs and investigators in the region.

In practice, there are no differences between biosimilar development requirements in Western Europe and those in CEE. However, substantial differences can be found in the requirements applicable for EU member states and non-EU territories.

Safety and Efficacy

Biosimilars are not innovative products as their development is based on similarity to reference medicinal products for which marketing authorisation has already been granted. The active substance of a biosimilar must be similar, in molecular and biological terms, to the active substance of the reference product. In addition, biosimilars cannot be defined as generics. Because of the complexity of biotechnologyderived products, subtle differences between biosimilars and reference products are acceptable, provided they do not significantly influence quality and efficacy.

The pharmaceutical form, strength and route of administration of the biosimilar product should be the same as that of the reference product, and any changes should be adequately justified. Any differences should not have a negative impact on patient safety; however, differences that could have an advantage with regard to safety may be applied. Nevertheless, intended changes to improve efficacy are not compatible with the biosimilarity approach (1).

A biosimilar medicinal product approach is based on comparability studies. The main goal for the manufacturer is to generate evidence of the highest level of similarity between biosimilar and reference product in terms of quality, safety and efficacy during preclinical and clinical stages. The development programme should be sensitive enough to detect any potential differences in quality of the products that may have an impact on efficacy and patient safety. Again, any observed differences should be adequately justified (2).

Regulatory Framework

The EU was the first region where the regulatory pathway for biosimilar medicinal products was established. The concept of a 'similar biological medicinal product' was adopted in EU pharmaceutical legislation in 2004 and came into effect in 2005. Based on this legal framework, the EMA published scientific guidelines to support the growth of biosimilar manufacturers. This includes overarching biosimilar guidance covering quality, non-clinical and clinical aspects of their development, as well as product class-specific guidelines (3).

In the CEE region, the EMA guidelines constitute the fundamental basis for biosimilar development and its harmonisation; however, many aspects must be considered and interpreted on a case-by-case basis. The guidelines have no legal force, and alternative approaches may be taken by biosimilar manufacturers, provided these are appropriately justified.

It is strongly recommended to consult the EMA in the event of any concerns, exemptions and deviations from the standard approach. This consultation should take place during the scientific advice procedure at early-stage product development. It may help prevent additional concerns and negative opinions at the time of submitting the marketing authorisation application.

Clinical Trial Design

The character and requirements of biosimilar clinical development are different to those for novel medicines. The main goal of biosimilars is to provide sufficient evidence of similarity to the reference product in terms of pharmacokinetic (PK) and pharmacodynamic (PD) parameters, efficacy and safety during a clinical comparability exercise – not to demonstrate patient benefits per se, as this has already been established for the original product.

The extent of clinical development is strictly dependent on the level of similarity of the quality profiles between similar and reference products observed during in vitro tests. Significant similarity in quality attributes of therapeutic molecules (such as affinity to target receptors, activity and purity), demonstrated by sensitive analytical tests, may enable a reduction in the development programme. Therefore, extensive state-of-the-art characterisation studies should be applied by biosimilar manufacturers to show, with a high level of assurance, that the quality of the similar biological medicinal product is comparable to the reference product (4).

Standard Pathway

According to the EMA guidelines, the standard clinical development pathway for biosimilars should begin with Phase 1 PK and PD studies, followed by comparative, equivalence, double-blind, randomised Phase 3 trials for the demonstration of comparable efficacy and safety in a large patient population (5). Phase 2 is not usually adequate or required to develop biosimilars, as the dose-response effect has already been established for the reference product.

It may be beneficial to add PD markers to the comparability PK studies. It is also feasible to perform PK/PD efficacy and safety assessments in parallel. Combined studies may provide useful information on the relationship between exposure and effect, and enable time and cost savings.

The relevant EMA guideline states that, in specific circumstances when the preclinical comparability tests (physicochemical characteristics, biological activity/potency, and PK and/or PD profiles) demonstrate significant similarity between biosimilar and reference product, and allow for the clear deduction of comparable safety and efficacy, confirmatory clinical trials may not be required (2).

It is not necessary to use the same end-points as used for the clinical development of reference medicinal product. There is also no need to show comparable PK, PD, efficacy and safety parameters in all indications licensed for the reference product. Not all end-points and patient populations used for the clinical development of originators will be found ideal to demonstrate similarity to reference product. It will be possible to choose only the most sensitive patient population for the clinical trial and to extrapolate therapeutic similarity to other indications of the reference product (6).

The design of clinical tests must be flexible and adaptable throughout the development of the product. For the sponsor and CRO, the most substantial concern is to choose the most sensitive disease model and clinical end-point to detect product-related differences in a homogeneous patient population where variability is limited, in order to increase precision of the final comparability assessment. The decision should be made based on clinical experience, literature data and thorough knowledge of the mechanisms of action in each indication.

Conduct and Recruitment

The biosimilar market – growing rapidly every year – is one of the most attractive targets for large, global pharmaceutical companies, as well as small biopharma manufacturers. Estimated patent expiry dates for major original biological products in Europe and the US are between 2013 and 2020. Patent expiration allows biosimilar manufacturers to launch their products on a particular market. In the CEE region (within the EU), marketing authorisations of biosimilars are granted under the EMA's centralised procedure – single marketing authorisation is valid in all EU countries.

The main goal for each biosimilar manufacturer is to be ready with a marketing authorisation application as soon as the regulatory path for the particular product is open, and before other competitive companies. Duration of clinical development plays a crucial role for products like biosimilars that are so promising and potentially lucrative for the industry. Prolonging clinical trials – for example, due to poor patient recruitment rates – and delays in marketing application submission may adversely affect future sales of products.

One of the main difficulties during the early stages of biosimilar clinical development is the selection of relevant sites and experienced investigators ready to recruit patients effectively in the expected timeframes. Precise feasibility assessment, and accurate selection of countries and sites, can guarantee future success of the trial. Choosing countries not saturated with clinical studies, and patient populations with limited access to advanced therapies, may be a solution.

Investigators should be adequately trained to fully understand the idea of biosimilarity, especially considering that the same efficacy and safety is expected for both biosimilar and reference products. Comprehensive evidence of a significant level of similarity obtained during the previous phases of development should be presented in a clear and understandable form.

The great number of biosimilar trials currently running make effective patient enrolment extremely diff cult, and thereby encourage sponsors and CROs to look for smart, innovative solutions and strategies to facilitate fast recruitment and reduce the time of clinical development.

Clinical protocols following the standard treatment programme may not be found as competitive and attractive for patients. At the time of clinical trial design, the sponsor and CRO should plan treatment procedures that encourage patients to be enrolled and participate until the end of the study. Precise procedures of monitoring patients' safety and efficacy should be implemented using state-of-the-art devices and techniques. The availability of long-term treatment and observation during follow-up may also influence patients' decisions positively.

Product Quality

Biologic medicinal products in the form of protein molecules are very sensitive to environmental conditions such as temperature, light and humidity. Special procedures should be implemented to ensure the required storage conditions are met, prevent any temperature deviations and loss of product stability during shipment, and facilitate storage and administration to patients.

Given that biologic products should be stored in adequate and validated cold chain conditions, it can be very challenging for multi-centre clinical trials in a number of countries to maintain the quality of the product throughout the course of the study, from manufacturing process through to final dispensation to patients.

Good Distribution Practice procedures should always be in place; storage conditions should be carefully monitored through the use of validated equipment and should be properly documented. Any deviations may cause increased risk to patient safety and signifi cant financial loss for the sponsor. Experienced and adequately trained medical personnel should be involved at all stages.

Controlled Conditions

Biologic products are usually manufactured as a lyophilisate or concentrate for preparation of solution for infusion. These products are typically administered intravenously, so particular attention should be given to maintaining aseptic conditions during preparation of the final formulation. Preparation of the solution for infusion should take place in controlled and validated aseptic conditions to ensure sterility.

In addition, biologic product infusions should be administered under the close supervision of experienced physicians, in an environment where full resuscitation facilities are immediately available, because of the potentially life-threatening infusion-related and hypersensitivity reaction.

Another difficulty that may be met during the trial is the applicable blinding of the biosimilar product in multi-centre, double-blind, randomised trials. The appearance of the investigational product should be the same as the reference product to assure credibility and accuracy of final assessment of clinical data. Ensuring the identical physical appearance of the substance and associated packaging materials may not be possible. In such cases, a dedicated unblinded site team may be needed for the study.

Despite the difficulties, challenges and risks related to biosimilars, manufacturers do not appear to be discouraged, if the market in the CEE region is any indication. Marketing approvals of reference biologic medicinal products have enabled the use of advanced targeted treatment. Looking ahead, marketing approvals of biosimilars will allow for the use of state-of-the-art therapies in everyday medical practice in CEE, where the level of reimbursement is usually lower, consisting of much more cost-effective alternatives to originators.

1. EMA/CHMP/437/04: Guideline on similar biological medicinal products, EMA, 2005
2. CHMP/437/04 Rev 1: Guideline on similar biological medicinal products, EMA, 2014
3. What you need to know about biosimilar medicinal product: A consensus information document, European Commission, 2013
4. EMEA/CHMP/BWP/49348/2005: Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Quality issues, EMA, 2006
5. EMEA/CHMP/BMWP/42832/2005: Guideline on similar medicinal products containing biotechnology-derived proteins as active substance: Non-clinical and clinical issues, EMA, 2006
6. EMEA/CHMP/BMWP/42832/2005 Rev 1: Guideline on similar medicinal products containing biotechnology-derived proteins as active substance: Non-clinical and clinical issues, EMA, 2013

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Magdalena Matusiak is Clinical Development Manager at KCR, a CRO and strategic solutions provider operating across 19 European countries, as well as the US. She specialises in the planning and coordination of clinical development, medical writing and scientific consultations with the EMA. Magdalena has extensive experience in the clinical development of biosimilars, especially biosimilar monoclonal antibodies.

Dr Anna Baran is a Vice President and Chief Medical Officer at KCR. She leads the organisation's early stages of study operations and provides cross-functional support to all KCR service areas, ensuring the smooth integration of medical affairs, regulatory and business development efforts. Throughout her career, Anna has worked closely with competent authorities across Eastern Europe, and has been involved in developing national legislation for clinical trials registration.
Magdalena Matusiak
Anna Baran
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