ICT Biosimilars

Like MindedThe clinical development of biosimilars can entail diffi culties and risks, but it remains big business for pharma. Central and Eastern Europe is certainly fi nding this to be the case, with manufacturers, CROs and investigators in this region relying on EMA guidelines when steering these products to market

between biosimilar and reference product in terms of quality,

safety and effi cacy 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 effi cacy and patient safety. Again, any

observed differences should be adequately justifi ed (2).

Regulatory Framework

The EU was the fi rst 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 scientifi c 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-specifi c 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

justifi ed.

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 scientifi c 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 suffi cient

evidence of similarity to the reference product in terms of

pharmacokinetic (PK) and pharmacodynamic (PD) parameters,

effi cacy and safety during a clinical comparability exercise –

The fi rst essential and fundamental stage of biosimilar product

development is a clear understanding of the specifi c nature

of these therapeutic proteins, as well as the demands relating

to proper planning, conduct and documentation in order to

facilitate future marketing authorisation.

Scientifi c 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 Effi cacy

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 defi ned

as generics. Because of the complexity of biotechnology-

derived products, subtle differences between biosimilars

and reference products are acceptable, provided they do

not signifi cantly infl uence quality and effi cacy.

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

justifi ed. 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 effi cacy 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

Magdalena Matusiak and Anna Baran at KCR

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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 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

About the authors

The great number of biosimilar trials currently running make

effective patient enrolment extremely diffi 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

effi cacy should be implemented using state-of-the-art devices

and techniques. The availability of long-term treatment and

observation during follow-up may also infl uence 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 fi nal

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 fi nancial 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 fi nal 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 diffi culty 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 fi nal 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 diffi culties, 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.

References1. EMA/CHMP/437/04: Guideline on similar biological medicinal products,

EMA, 20052. CHMP/437/04 Rev 1: Guideline on similar biological medicinal

products, EMA, 20143. What you need to know about biosimilar medicinal product:

A consensus information document, European Commission, 20134. 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

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 scientifi c consultations

with the EMA. Magdalena has extensive experience in the clinical development of biosimilars, especially biosimilar monoclonal antibodies.

Email: magdalena.matusiak@kcrcro.com

Dr Anna Baran is a Vice President and Chief Medical Offi cer 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.

Email: anna.baran@kcrcro.com